Information

10.2C: Extent of Host Involvement - Biology


Host-pathogen interactions are the interactions taking place between a pathogen (e.g. humans, plants).

Learning Objectives

  • Differentiate between primary and opportunistic pathogens in regards to host involvement

Key Points

  • All pathogens damage their host to some extent, usually resulting in an infectious disease from the interplay between the pathogens and the defenses of the hosts they infect.
  • Clinicians classify infectious microorganisms or microbes according to the status of host defenses – either as primary pathogens or as opportunistic pathogens.
  • Primary pathogens cause disease as a result of their presence or activity within the normal, healthy host, and their intrinsic virulence is, in part, a necessary consequence of their need to reproduce and spread.
  • Organisms which cause an infectious disease in a host with depressed resistance are classified as opportunistic pathogens.

Key Terms

  • host: A cell or organism which harbors another organism or biological entity, usually a parasite.
  • pathogen: Any organism or substance, especially a microorganism, capable of causing disease, such as bacteria, viruses, protozoa, or fungi. Microorganisms are not considered to be pathogenic until they have reached a population size that is large enough to cause disease.

Host-pathogen interactions are the interactions that take place between a pathogen (e.g. virus, bacteria ) and their host (e.g. humans, plants). By definition, all pathogens damage their host to some extent. Infectious diseases result from the interplay between the pathogens and the defenses of the hosts they infect. The appearance and severity of disease resulting from the presence of any pathogen depends upon the ability of that pathogen to damage the host as well as the ability of the host to resist the pathogen.

Clinicians therefore classify infectious microorganisms or microbes according to the status of host defenses – either as primary pathogens or as opportunistic pathogens.

Primary pathogens cause disease as a result of their presence or activity within the normal, healthy host, and their intrinsic virulence is, in part, a necessary consequence of their need to reproduce and spread. Many of the most common primary pathogens of humans only infect humans; however many serious diseases are caused by organisms acquired from the environment or which infect non-human hosts.

Organisms which cause an infectious disease in a host with depressed resistance are classified as opportunistic pathogens. Opportunistic diseases may be caused by microbes that are ordinarily in contact with the host, such as pathogenic bacteria or fungi in the gastrointestinal or the upper respiratory tract, and they may also result from (otherwise innocuous) microbes acquired from other hosts or from the environment as a result of traumatic introduction. An opportunistic disease requires impairment of host defenses, which may occur as a result of several factors such as genetic defects, exposure to antimicrobial drugs or immunosuppressive chemicals, exposure to ionizing radiation, or as a result of an infectious disease with immunosuppressive activity. Primary pathogens may also cause more severe disease in a host with depressed resistance than would normally occur in an immunosufficient host.


Kalytera’s Cannabidiol Prevents Graft-Versus-Host-Disease After Bone Marrow Transplant, Data Show

Kalytera’s cannabidiol (CBD) compound efficiently prevents graft-versus-host disease (GVHD) in patients receiving bone marrow transplants from matched unrelated donors, interim data from a Phase 2 study show.

Considering the study’s positive results so far, the company announced that it will halt the Phase 2 study and proceed directly to initiate a Phase 3 clinical trial.

Bone marrow transplant is one of the most effective curative treatments for patients with blood cancers, such as multiple myeloma. However, it comes with great risk of acute GVHD, a life-threatening condition that happens when the transplanted donor immune cells see the recipient’s body as foreign and react against it.

Acute GVHD usually occurs within the first 100 days post-transplant and causes skin rash, liver problems, and intestinal symptoms such as nausea and diarrhea.

It is estimated that up to 50% of patients receiving bone marrow transplants from a sibling donor, and 60%–70% of patients receiving the transplant from a matched unrelated donor, will develop grade 2–4 GVHD. Acute GVHD grades go from 0 to 4 according to number and extent of organ involvement.

There are no approved therapies for the prevention of acute GVHD current therapeutic strategies commonly rely on the suppression of the immune system, which can lead to severe infections.

Thus, the development of efficient therapies to prevent acute GVHD is a major goal of modern bone marrow transplantation medicine.

Kalytera’s new, proprietary CBD product is an oral formulation in olive oil designed to overcome CBD’s issues of poor oral bioavailability and stability. CBD is a non-psychoactive component of cannabis with immunosuppressive properties.

The company’s open-label, multi-center, Phase 2 study (NCT03840512) was designed to evaluate the efficiency and safety of three oral doses of CBD (75, 150, or 300 mg twice a day) in the prevention of acute GVHD in patients receiving bone marrow transplants from matched unrelated donors.

So far, 24 patients were enrolled and received either the low dose (12 patients) or the medium dose (12 patients) of CBD for 105 days following bone marrow transplant. Participants were followed for an additional 80 days after treatment cessation.

The interim results showed that only one patient receiving the low dose of CBD (8%) and no patients in the medium dose group developed grade 2–4 acute GVHD. The GVHD developed by the patient in the low-dose group was grade 2, a non-serious form of the disease.

The pronounced reduction in the frequency of acute GVHD from a historic norm of 60%–70% to less than 10% in patients receiving bone marrow transplants from matched unrelated donors suggests that Kalytera’s CBD is a strong therapeutic candidate for this disease.

“We did not expect the results from the low-dose cohort [group] to be as positive as they were, and now we have interim results from the medium-dose cohort that are equally as good,” Robert Farrell, Kalytera’s president and CEO, said in a press release.

The results were consistent with data from two previous clinical studies involving 60 patients receiving bone marrow transplants from matched unrelated donors. In those studies, a total of two patients developed grade 2–4 GVHD while receiving CBD.

Farrell stated that the company believes these data “exceed what will be required in a Phase 3 registration study to demonstrate the efficacy of CBD in prevention of acute GVHD, and leave little or no room for improvement with the high dose,” and that it has “decided to halt the ongoing Phase 2 clinical study without enrolling the high-dose cohort, and proceed directly to initiate a Phase 3 clinical registration study.”

The multinational, double-blind, placebo-controlled Phase 3 study is expected to enroll 50 patients, who will be randomly selected to receive either a 150-mg dose of CBD or a placebo twice daily for approximately 100 days. The study will last approximately 12 months.

Enrollment will start at the same clinical sites in Israel and Australia where the Phase 2 trial is being conducted, then will be expanded to one or two additional sites in both the United States and Europe.

Kalytera believes the results of the Phase 3 study will meet the requirements for CBD approval by regulatory agencies around the world, potentially making its CBD product the first approved therapy for prevention of acute GVHD following bone marrow transplantation.

The company plans to present the results of the Phase 2 study, along with findings on the mechanism of action of CBD in the prevention and treatment of acute GVHD, at upcoming scientific meetings and to submit those data for publication.


Regular Wounding in a Natural System: Bacteria Associated With Reproductive Organs of Bedbugs and Their Quorum Sensing Abilities

During wounding, tissues are disrupted so that bacteria can easily enter the host and trigger a host response. Both the host response and bacterial communication can occur through quorum sensing (QS) and quorum sensing inhibition (QSI). Here, we characterize the effect of wounding on the host-associated bacterial community of the bed bug. This is a model system where the male is wounding the female during every mating. Whereas several aspects of the microbial involvement during wounding have been previously examined, it is not clear to what extent QS and QSI play a role. We find that the microbiome differs depending on mating and feeding status of female bedbugs and is specific to the location of isolation. Most organs of bedbugs harbor bacteria, which are capable of both QS and QSI signaling. By focusing on the prokaryotic quorum communication system, we provide a baseline for future research in this unique system. We advocate the bedbug system as suitable for studying the effects of bacteria on reproduction and for addressing prokaryote and eukaryote communication during wounding.

Keywords: genital infection genitalia-associated microbes interspecific communication quorum quenching reproductive immunity.

Figures

Phylogenetic tree [RAxML rapid bootstrap…

Phylogenetic tree [RAxML rapid bootstrap (35)], reconstructed for the 16s rDNA gene sequences…

Distribution of cultivated bacteria with…

Distribution of cultivated bacteria with respect to female mating status, bedbug tissue, and…

Area of zones in square millimeters for each assay type and bacteria species…

Proportion of mesospermaleges—the site of…

Proportion of mesospermaleges—the site of regular wounding—from mated and virgin females from which…


Immunity to Infection

Iii) Defense against Ectoparasites

Ectoparasites are often arthropods that attack the exterior surface of a host. For example, the common tick is the carrier of the extracellular bacterium Borrelia burgdorferi responsible for Lyme disease. The bacteria are introduced into the host when the tick bites him/her to obtain a blood meal. Large numbers of basophils, eosinophils and mast cells accumulate at the bite site to repel both the attacking bacteria and the tick. It is thought that when mast cell degranulation releases substances that increase vascular permeability, ticks have greater difficulty in locating host blood vessels. Some ectoparasites are countered by the same strategies effective against helminth worms. Antipathogen IgE bound to the surface of basophils and mast cells is critical for host defense against such invaders. For example, humans who lack adequate numbers of basophils and eosinophils develop scabies, a severe, itchy rash caused by the mite Sarcoptes scabiei. Much remains to be determined about the molecular details of immune responses to ectoparasites.

NOTE: The involvement of Th2 responses in defense against ectoparasites came from the unexpected finding of increased Demodex skin infections in mice lacking both CD28 and STAT6. CD28 is a key costimulator of Th cell activation, and STAT6 is the transcription factor required for IL-4 production by these cells.


Histopathology

In the gastrointestinal tract, apoptosis of epithelial cells is the most important feature. Dilated crypts, crypt destruction, villus atrophy, neutrophilic infiltration can also be seen in small bowel specimens [11]. Liver biopsy shows dysmorphic small bile ducts with portal inflammation. Histopathological damage of the skin ranges from minimal vacuolization to separation of the dermis from the epidermis. Grades of skin graft-versus-host-disease are as follows (Figure 2): [12]


SARS-CoV-2 virus and liver expression of host receptors: Putative mechanisms of liver involvement in COVID-19

Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET)−University of Buenos Aires, Buenos Aires, Argentina

School of Medicine, Institute of Medical Research A Lanari, University of Buenos Aires, Buenos Aires, Argentina

Department of Clinical and Molecular Hepatology, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET)−University of Buenos Aires, Buenos Aires, Argentina

Carlos J. Pirola and Silvia Sookoian, Instituto de Investigaciones Médicas, IDIM-CONICET, Combatientes de Malvinas 3150, CABA-1427, Argentina.

School of Medicine, Institute of Medical Research A Lanari, University of Buenos Aires, Buenos Aires, Argentina

Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET)−University of Buenos Aires, Buenos Aires, Argentina

School of Medicine, Institute of Medical Research A Lanari, University of Buenos Aires, Buenos Aires, Argentina

Department of Clinical and Molecular Hepatology, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET)−University of Buenos Aires, Buenos Aires, Argentina

Carlos J. Pirola and Silvia Sookoian, Instituto de Investigaciones Médicas, IDIM-CONICET, Combatientes de Malvinas 3150, CABA-1427, Argentina.

Zhang et al showed that COVID-19 affected patients' present liver biochemistry abnormalities, including elevation of aminotransferases, gamma-glutamyl transferase and alkaline phosphatase. 1 Hence, several possible clinical scenarios in the setting of liver diseases have been postulated. First, patients with chronic liver disease may be more vulnerable to the severe clinical consequences of COVID-19, including oxygen desaturation and hypoxemia due to severe pneumonia or the cytokine storm. 1, 2 Second, liver biochemistry abnormalities are the consequence of drug toxicity.

There is a third potential but poorly explored clinical scenario, which is the possibility that the novel 2019 coronavirus, also known as SARS-CoV-2, may directly or indirectly cause liver injury. In fact, SARS-CoV2 viral load in the stool, which has been detected in about 48% of patients even in stool collected after respiratory samples tested negative, 3 is likely to be associated with portal venous viraemia.

We assessed the gene expression levels of SARS-CoV2-interacting host receptors in the liver tissue and their distribution across cell types according to single-cell transcriptomic experiments retrieved from the Single Cell Portal. We focused on angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2) and paired basic amino acid cleaving enzyme (FURIN) gene expression levels. Our analysis shows that the three human host receptors are expressed in the liver tissue however, expression levels extensively vary across cell types. ACE2 presents the highest expression levels in cholangiocytes, followed by hepatocytes (Figure 1C). TMPRSS2 is expressed in cholangiocytes, hepatocytes, periportal liver sinusoidal endothelial cells, erytroid cells, and in a much lesser extent in non-inflammatory macrophages and alpha-beta T cells (Figure 1D). FURIN shows expression levels across all cell types, from hepatocytes to all populations of liver resident cells (Figure 1E).

Together, these findings support the possibility that SARS-CoV-2 may cause direct liver injury by viral cytopathic effect (directly by lysis and/or by inducing necrotic/apoptotic effect/s). Furthermore, the expression pattern in cell clusters associated with numerous active immune pathways, for example, inflammatory macrophages, natural killer cells, plasma cells, mature B cells and cells of the liver endothelial microenvironment, opens the possibility of SARS-CoV-2 -immune-mediated liver damage.

Not surprisingly, reports from the past 2003-SARS (severe acute respiratory syndrome) epidemic showed not only liver impairment in up to 60% of the patients but also confirmed the presence of SARS-coronavirus by RT-PCR in liver biopsies presenting mild to moderate lobular inflammation and apoptosis. 4

In conclusion, to understand the pathogenesis of SARS-CoV-2–related liver disease, additional research must be guaranteed, including the search for evidence of viral replication in hepatocytes and liver histology characterization.


Polymers in Biology and Medicine

9.23.5.1.2 DNA stretching

DNA can also be patterned by stretching or extending it along a surface. DNA stretching can be accomplished using the force exerted at a receding air–water interface on a hydrophobic surface (molecular combing) 70 and confinement of the stretched DNA in nanochannels. 71 Stretching DNA in nanochannels has several advantages over other techniques. First, external force is not required because long DNA molecules tend to spontaneously elongate and enter nanochannels directly from the environment due to the large free energy and reduction in entropy. Second, continuous measurement of the entire length of DNA can be achieved by alignment of the DNA molecule in nanochannels with dimensions comparable to the size of biological macromolecules (typically with a dimension below 100 nm). Stretched DNA can also be useful in DNA sequencing. In shotgun DNA sequencing, the location of landmark restriction sites on chromosomal length DNA molecules is a powerful method to ensure a faithful representation of the assembled DNA sequences to the intact genome. 72 The restriction sites can be determined by gel electrophoresis 73 or alternatively by optical mapping of the stretched DNA molecules. 71 DNA stretching is important to ensure one-to-one mapping between the spatial position along the DNA molecules and the position within the genome using optical techniques. 74 Stretched DNA has also been used to investigate DNA–protein interactions at the single molecule level. This technique has been used increasingly to quantify distributions of molecular and mechanical properties, transient intermediates, and reaction pathways. 54 Once again, stretching and immobilization of DNA molecules is required to suppress Brownian motion so that protein motion along the DNA contour can be clearly tracked.


Endophytes: Colonization, Behaviour, and Their Role in Defense Mechanism

Biotic and abiotic factors cause an enormous amount of yield and economical loss. However, endophytes can play a significant role in enhancing the tolerance of plants. Endophytes systematically colonize different parts of the host, but plants use a variety of defense mechanisms towards microbial infection. However, they have to survive the oxidative environments, and endophytes like Enterobacter sp. encode superoxide dismutases, catalases, and hydroperoxide reductases to cope up the oxidative stress during colonization. On the contrary, others produce subtilomycin which binds with flagella to affect flg22-induced plant defense. The behavior of endophytes can be affected by different genes in hydrolase activity when they come into contact with the host plant. The lifestyle of endophytes is influenced by environmental factors, the host, and microbial genotypes, as well as an imbalance in nutrient exchange between the microbe and the host. For instance, induction of PiAMT1 in root endophyte Piriformospora indica indicates depletion of nitrogen which plays as a triggering factor for activation of the saprotrophic program. Microbes enhance disease resistance through induced systemic resistance (ISR), and Bacillus cereus triggers ISR against Botrytis cinerea through an accumulation of the PR1 protein and activates MAPK signaling and WRKY53 gene expression by the JA/ET signaling pathway. Similarly, Trichoderma arundinaceum produces trichodiene that affects Botrytis cinerea through induction of defense-related genes encoding salicylic acid (SA) and jasmonate (JA). Overall, endophytes can play a vital role in disease management.

1. Introduction

Crops are colonized by complex microbial communities [1], and some of them are detrimental and cause diseases, whereas others promote plant growth and enhance nutrient acquisition and tolerance to biotic and abiotic stresses via a multitude of mechanisms [2]. The fungi or bacteria which grow inside the plant tissue without causing any harm to the host are termed as endophytes. They associate with the majority of plant species found in natural and managed ecosystems. Endophytes are considered as important plant partners that play an important role in improving stress tolerance of the host compared to those that lack such symbiosis [3, 4]. Most endophytes are found without any known effect, but numerous bacteria and fungi establish a mutualistic or pathogenic association with the host plant. Mostly, the outcome of interactions relies on the environmental factors, the genotype of both the host and the interacting microorganism [2].

Plants could sense microbes via the perception of microbial-/pathogen-associated molecular patterns (MAMPs/PAMPs) by pattern-recognition receptors (PRRs). PRRs are classes of cell surface recognition proteins involved in initial signaling that trigger the first layer of plant innate immunity. Flagellin protein (flg22) and elongation factor Tu (EU-Tu) are the two most well-characterized MAMPs/PAMPs [5]. In general, during the establishment of symbiosis, most of the pathways targeted by miRNAs for plant defense systems are turned off that would otherwise have obstructed proliferation of endophytes [6].

Endophytes are found in all plant species regardless of their place of origin. The ability to enter and thrive in the host tissues makes them unique, showing multidimensional interactions within the host plant. Several host activities are known to be influenced by the presence of endophytes. They can promote plant growth, elicit defense response against pathogen attack, and can act as remediators of abiotic stresses [7]. Overall, fossil records of endophytes date back to more than 400 million years, implicating these microorganisms in host plant adaptation to habitat transitions [4].

2. Colonization Mechanism

Microbes, whether they are beneficial or plant pathogens, have similar potentials like rhizosphere competence, motility to reach the host plant, mechanisms for entrance and spreading inside the plant, and the ability to overcome plant immunity [8, 9]. Successful colonization by endophytes is affected by different factors including the plant tissue type, the plant genotype, the microbial taxon and strain type, and biotic and abiotic environmental conditions [1]. Similarly, growth medium, plant age and species, inoculum density, and fungal species, as well as the rate of conidia application, affect endophytic colonization [10]. Bamisile et al. [11] reported the influence of seedling age on B. bassiana and M. anisopliae successful colonization in the citrus plant. From their point of entry, microbes may systemically colonize plants from roots to shoots, shoots to flowers or fruits, and/or from flowers to fruits and seeds, and they may also cause localized colonization inside/outside plant organs [12]. Colonization of olive (Olea europaea L.) through root hair with Pseudomonas fluorescens PICF7 and P. putida PICP2 enables the plant to withstand soil-borne fungal pathogen Verticillium dahliae Kleb [13]. On the contrary, in berries, some Firmicutes and Bacillus spp. are reported to colonize cell walls of the seed endosperm and consistently found inside flower ovules as well as in the pulp and inside seeds [14]. Thereby, the colonization of endophytes is organ- and tissue-specific due to selective pressure. This tissue specificity in colonization leads to tissue-specific protection from diseases [15, 16].

Plants use a variety of defense mechanisms against microbial infection, and the response of the host plant drastically differs to the colonization of endophytes and a pathogen. Prior to colonization, microbes have to survive the oxidative environments within the host plant. For instance, Enterobacter sp. encode superoxide dismutase, catalases, and hydroperoxide reductases to cope up the oxidative stress during colonization of poplar (Populus trichocarpa×deltoides cv. H11-11) [17]. Chen et al. [18] reported rice blight Xanthomonas oryzae pv. oryzae PXO99 induced a much stronger defense reaction than the endophyte Azoarcus olearius in rice plants. Surprisingly, differentially expressed genes (DEGs) related to the jasmonate (JA) signaling pathway are constantly activated by beneficial endophytes in contrast to the salicylate (SA) pathway which is activated only in rice roots of infected plants by the pathogen indicating that JA is involved in controlling the Azoarcus endophyte density in roots. In Arabidopsis thaliana, endophyte bacterium Bacillus subtilis BSn5 produces subtilomycin which affects flg22-induced plant defense by binding with flagellin and ultimately enhances its ability to colonize plant endosphere [19].

Endophytic strain Serratia plymuthica G3 and QS genes control important colonization-related traits such as swimming motility and biofilm formation. Likewise, genes for superoxide dismutases, putative catalases, peroxidases, and reductases are used by diazotrophic Klebsiella pneumoniae (Kp) 342 to protect its cells against plant ROS [20]. On the contrary, in sugarcanes, the shr5 gene is differentially expressed to the colonization of beneficial and nonbeneficial microbes. This gene encodes a protein involved in plant signal transduction during the establishment of plant-endophyte interactions. Downregulation of shr5 occurred exclusively when inoculated with beneficial bacteria like Gluconacetobacter diazotrophicus [5]. According to Kandel et al. [21], during the early stages of rice root colonization, an endophytic bacterium Gluconacetobacter diazotrophicus also expressed ROS-deactivating genes such as superoxide dismutase (SOD) and glutathione reductase (GR) in greater amounts. Likewise, endoglucanase plays a major role in endophytic colonization. An eglA mutant failed to efficiently invade the plant cells and systematically colonize the plant, in contrast to the wild-type strain. Azoarcus sp. endoglucanase is an important determinant for successful endophytic colonization of rice roots [20, 22].

3. Endophytic Behavior

Most plant pathogens carry genes encoding plant cell wall-degrading enzymes. However, nonphytopathogens may possess glycoside hydrolase other than cellulase/hemicellulase (or cell wall degradation hydrolases). The presence of this enzyme in numerous endophytes is consistent with its possible role in the diversity of sugar utilization that might be a useful component of a competent endophyte [23]. According to Taghavi et al. [17], the genome of Enterobacter sp. does not encode proteins involved in cellulose degradation, which is consistent with its nonpathogenic behavior, during the interaction of the endophyte and the poplar tree. The endophytic behavior can be affected by different genes that are found to be conserved including various transcriptional regulators. For example, the presence of the LrgB family protein is mainly involved in controlling hydrolase activity whose most likely function occurs when endophytes come into contact with plant hosts at the time of plant infection [23].

Protein secretion plays a major role in defining plant-microbe interactions. The transport of effector proteins plays an important role in the parasitic lifestyle of bacteria by suppressing host defense, whereas the effector-triggered immune responses are stimulated by the host whenever it recognizes the effector proteins. Particularly important in this context are the T3SSs and T4SS [24] (Figure 1). On the contrary, genes for T3SSs are largely missing or incomplete in genomes of mutualistic endophytes. They can be considered as disarmed pathogens that lost their functional T3SSs, and they evolved to an endophytic lifestyle. For instance, T3SS mutants of Salmonella enterica showed increased endophytic colonization in Medicago truncatula. Generally, Type I and Type II secretion systems are present in several bacterial endophytes [2, 9], but Type III and Type IV secretion systems are mainly present in pathogenic bacteria and are mostly absent in endophytes [23, 26].

The plant receptor FLS2 recognizes flagellin of bacteria and initiates plant defense. It has been reported that the recognition of P. syringae flagellin in Arabidopsis and Nicotiana benthamiana triggered stomata closure [27] and activation of MAP kinase [2]. This leads to transcriptional induction of pathogen-responsive genes, production of reactive oxygen species, and deposition of callose to reinforce the cell wall and prevent microbial growth at infection sites. However, flagellin of the mutualist endophyte Paraburkholderia phytofirmans PsJN triggered a weak and transient defense reaction with an oxidative burst but to a lower extent compared to pathogenic interactions [2, 28, 29]. In line with this, the downregulation of flagella biosynthesis and upregulation of functions related to flagellar motor rotation assist endophytes to hide their flagellin PAMPs and move faster in plant environment, whereas downregulation of elongation factor EF-Tu enabled the colonization of rice by endophytic bacteria [30].

LPSs are also known to induce different host responses for pathogens and nonpathogen endophytes. LPSs from the plant beneficial strain of P. phytofirmans PsJN can downregulate defense genes, such as defense-like PR1, superoxide dismutase, and the COP9 signalosome complex in potato leaves which indicates that plants can identify LPSs derived from nonpathogenic endophytes [2]. Overall, genes putatively involved in antibiotic resistance (evgS and evgA), redox response (regB and regA), nitrogen fixation and metabolism (ntrY and ntrX), and cell fate control (pleC and pleD) are found more prominently among endophytes than among phytopathogens [1].

4. Switch among Lifestyle in Fungi

Fungi use different survival strategies and lifestyle patterns after entering into the plant system to associate intimately with the plants. Endophytes profit from host plants by receiving organic nutrients, protective shed, and guaranteed transmission to the next host generation on the contrary, infected host plants are more vital, stress-resistant, and toxic to herbivores, nematodes, and pathogens [3]. The fungal endophytes have a broad host range, and they may choose one of the many strategies for entering into the host internal system such as the production of toxic metabolites, modification of plant elicitors, and suppressing the plant immune system [31]. Host preference is an important parameter for both parasitic and symbiotic plant-fungal interactions [32], and it originates from the close adaptation between the host plant and its fungal partner through cohabitation and coevolution, which finally leads to stronger partnership and is permanently imprinted in the genetic constitution of both partners.

Host and microbial genotypes are the most important factors responsible for the expression of a particular lifestyle. The interaction can be considered as a flexible interaction, whose directionality, to some extent, is determined by slight differences in the fungal gene expression in response to the host and also by host recognition and response to the fungus. Several studies examining the relation between the host genotype and the symbiotic lifestyle expression demonstrated that individual isolates of some fungal species could express either parasitic or mutualistic lifestyles depending on their host genotype [33]. The genetic and biochemical base of a fungal lifestyle change from endophytic to parasitic is characterized by an imbalance in the nutrient exchange between the plant and the fungus. According to Rai and Agarkar [3], UV mutagenesis of a virulent isolate (CmL2.5) of C. magna leads to the enhancement of host plant fitness to disease and drought. Similarly, asymptomatic endophyte Diplodia mutila switches its lifestyle to pathogenic. Alvarez-Loayza et al. [34] reported that high light triggers endophyte pathogenicity, while low light supports endosymbiotic development. The pathogenicity under high light resulted from light-induced production of H2O2 by the fungus, triggering hypersensitivity, cell death, and tissue necrosis. Their study demonstrated that endophytes respond to abiotic factors to influence plant-fungal interactions in natural ecosystems, and the light was identified as the influencing factor. In general, changing of lifestyle from endophytic to pathogenic or vice-versa when colonizing its host might be due to the disruption of a balanced communication with its host factor [35].

The root endophyte Piriformospora indica requires the provision of an adequate source of nitrogen to induce low expression of the P. indica high-affinity ammonium transporter during host colonization [36]. On the contrary, the induction of PiAMT1 indicates the depletion of nitrogen which plays as a triggering factor for the in planta expression of fungal genes that encode hydrolytic enzymes for the activation of the saprotrophic program. Silencing of PiAMT1 results in reduced expression of fungal xylanase and host’s defense response. Hence, the expression and a signaling function of PiAmt1 are needed for the switch of P. indica’s lifestyle to saprotrophy [37]. The disruption of communication between Pinus sylvestris and Neurospora crassa plays a role in changing the lifestyle from endophytic to pathogenic [35]. Disruption of components of the Nox complex (NoxA, NoxR, and RacA), or stress-activated MAP kinase (SakA), leads to a breakdown in this finely balanced association, resulting in pathogenic infection instead of mutualism. In the sakA mutant association, a dramatic upregulation of fungal hydrolases and transporters was observed, changes consistent with a switch from restricted symbiotic to proliferative pathogenic growth [38]. Sometimes, a microbe varies its association with different hosts. Temporal induction of genes, carbohydrate-active enzymes (CAZymes), and necrosis-inducing effectors plays a vital role in infection and colonization of hosts. Fusarium virguliforme effectors and CAZymes are expressed in temporal distinct waves immediately after infection in the soybean-infected root compared to maize. On top of that, the upregulation of Zn(II)-Cys6 genes during early soybean colonization might play a role in the enhancement of pathogenicity of F. virguliforme on soybean [39].

5. Induction of Plant Disease Resistance

Endophyte microbiomes are known to significantly influence host performance especially under stressed conditions [40, 41] and mediate functioning of the plant microecosystem by critically altering the responses of the plant to environmental changes [42]. Endophytes have to compete with plant cells for Fe supply, and therefore, siderophore production is highly important for endophytic growth through increasing availability of minerals in addition to iron chelation and also involved in suppression of pathogens by stimulating the biosynthesis of other antimicrobial compounds [43–45]. Extensive multiplication and colonization of plant tissues by endophytes result in a “barrier effect,” where the existing endophytes compete with the pathogenic microorganisms and prevent them from taking hold. Similarly, endophytes play an imperative role to maintain the health of plants, through antibiosis or induced systemic resistance, as they can protect or prepare the plant against biotic stresses and help in enhancing growth and yields [46].

Microbes enhance disease resistance through the mechanism of induced systematic resistance (ISR) and systemic acquired resistance (SAR) [47]. Microbe- or pathogen-associated molecular patterns (MAMPs/PAMPs) are essential structures that are conserved and necessary for microbial survival, but plants have evolved multiple families of receptor proteins to recognize them and induce the plant immune system [6] (Figure 2). Pattern-recognition receptors (PRRs) have evolved to recognize common microbial compounds, such as bacterial flagellin or fungal chitin, called pathogen- or microbe-associated molecular patterns (PAMPs or MAMPs). Pattern recognition is translated into a first line of defense called PAMP-triggered immunity (PTI), which keeps the most potential invaders under control [2].

Tomato and cotton seed treatment with Beauveria bassiana induced protection against Pythium myriotylum and Rhizoctonia solani [10]. Similarly, Beauveria bassiana is known to induce Citrus limon plant resistance to an insect pest Diaphorina citri [48]. Endophytic fungus Lecanicillium longisporum suppresses powdery mildew and aphids in cucumber plants [10]. The endophyte Bacillus cereus triggers ISR against Botrytis cinerea on Arabidopsis thaliana through an enhanced accumulation of the PR1 protein expression on time, hydrogen peroxide accumulation, and callose deposition. Mitogen-activated protein kinase (MAPK) cascades play a crucial role in the biotic as well as abiotic stress response through decoding external stimuli and signal transduction [49]. Endophyte activates MAPK signaling and the WRKY53 gene expression, both of which are involved in the pathogen-associated molecular pattern- (PAMP-) triggered immunity (PTI) by the JA/ET signaling pathway in an NPR1-dependent manner [50]. The bacterial endophyte Azospirillum sp. also induces systemic disease resistance in rice against rice blast, and ET signaling is required for endophyte-mediated induced systemic resistance (ISR) in rice [51]. Overall, the combination of jasmonic acid (JA) and ethylene (ET) signaling activates resistance against necrotrophic pathogens, whereas salicylic acid (SA) signaling triggers resistance against biotrophic and hemibiotrophic pathogens [52].

Endophytes induce several cell wall modifications, such as deposition of callose, pectin, cellulose, and phenolic compounds, leading to the formation of a structural barrier at the site of a potential attack by phytopathogens. Similarly, they induce defense-related proteins such as peroxidases, chitinases, and β-1,3-glucanases [20]. Trichoderma arundinaceum produces VOCs like trichodiene that affects Botrytis cinerea through induction of the expression of tomato plant defense-related genes encoding salicylic acid (SA) and jasmonate (JA) [53]. Barley inoculated with oxo-C14-homoserine lactone (AHL) producing Ensifer meliloti enhances the resistance against Puccinia hordei [54]. The genome analysis of the endophytic biocontrol strain of Pseudomonas chlororaphis subsp. aurantiaca PB-St2 revealed the presence of acyl-homoserine lactone (AHL) biosynthesis genes phzI, csaI, and aurI involved in clear AHL production which might have a role for biocontrol activity [55]. Similarly, endophytic Pseudomonas putida modified with an antifungal phz gene obtained from Pseudomonas fluorescens plays a major role in the reduction of the fungal population on soils in wheat field [56].

Lipid transfer protein (LTP) plays a role in plant responses to biotic and abiotic stress. LTP1 binds jasmonic acid, and together, they compete with a stronger affinity for the elicitin binding site and are capable of inducing resistance at a distance from the point of application. Expression of CaLTP-N, encoding an LTP-like protein, reduced disease development, suggesting LTP is a functional component of resistance induced by Trichoderma species to Phytophthora infection in hot pepper [57]. The endophyte fungi Penicillium citrinum LWL4 and Aspergillus terreus LWL5 reduced fungal infection caused by Alternaria alternata in the sunflower plant by regulating oxidative stress responses by activating glutathione and polyphenol oxidase and downregulating catalase and peroxidase. Similarly, the amino acid content was higher on leaves inoculated with endophytes which suggests such change delays cell death and disturbs fungal progression in the plant tissue [58].

Seed-borne endophytic microbe Bacillus amyloliquefaciens RWL-1 induces disease resistance against pathogenic Fusarium oxysporum f. sp. lycopersici in the tomato plant through activation of amino acid biosyntheses like aspartic acid, glutamic acid, serine (Ser), and proline (Pro). They are important in the induction of plant defense during pathogenesis. Pro plays a role in strengthening of the cell wall during pathogen attack [59]. The level of defense-related oxidative enzymes like phenyl ammonia lyase (PAL), Polyphenol oxidase (PPO), and peroxidase (PO) was higher on tomato plants treated with bacterial endophytes which resulted in induced systemic resistance against Fusarium wilt of tomatoes [60, 61].

6. Conclusion

Successful establishment of endophytes within the host is affected by the tissue type, the genotype of the host, and microbe, as well as the environmental conditions. Crops colonized by endophytes have a high tendency to stress tolerance than those that lack such symbiosis. Most pathways targeted by miRNAs for plant defense are turned off during the establishment of symbiosis. Similarly, genes involved in anabolic pathways are more diverse and abundant among endophytes in contrast to phytopathogens. The endophytic behavior can be affected by different genes that are found to be conserved including various transcriptional regulators. Sometimes, endophytes can downregulate flagella biosynthesis and upregulate functions related to flagellar motor rotation to hide their flagellin PAMPs and move faster within plants during colonization. Endophytes use different survival strategies and lifestyle patterns after entering into the plant. They will change their lifestyle into pathogenic whenever an imbalance occurred during the host-microbe interaction.

Endophytes are known to influence host performance under stress conditions by altering the response of the plant to environmental change. They can act as a barrier as well as compute with pathogenic microorganisms and prevent them from taking hold. Similarly, through antibiosis or induced systemic resistance, they can maintain the health of the plant and assist in enhancing growth and yields. Jasmonic acid (JA) and ethylene (ET) as well as salicylic acid (SA) signaling is required for endophyte-mediated induced resistance. On the contrary, endophytes can induce disease resistance through the activation of amino acid biosynthesis. Overall, endophytes are regarded as extremely important plant partners with the potential to minimize the yield loss through the provision of improved stress tolerance to the host in an environmentally friendly manner and thereby enhance the productivity of agriculture.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest

The author declares that there are no conflicts of interest.

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Copyright

Copyright © 2020 Anteneh Ademe Mengistu. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Seasonality shapes coevolution of parasites and hosts

Parasites and their hosts coevolve in an arms race influenced by environmental conditions. Seasonal change, for example, can shape the course of evolution, but precisely how has been something of a mystery. A recent study used lab experiments and mathematical modeling to tease out one potentially important pattern: the intensity of this coevolution peaks when the extent of seasonal change is moderate rather than mild or extreme.

The study, published in Proceedings of the Royal Society B, showed that the bacterium Pseudomonas fluorescens and its associated bacteriophage, SBW25φ2, evolved their strongest defenses and infectivity when the host and parasite grew together in media with moderately fluctuating nutritional values, representing seasonality over time. While coevolution is a classic topic in ecology, the effect of seasonal environmental variation is less well understood and rarely experimentally tested, notes coauthor Charlotte Ferris, who led the study as a mathematics PhD student at the University of Sheffield in the United Kingdom.

Ferris had previously published a 2018 theoretical study that used a classic epidemiological model to predict the progress of an infection through a host community. That model assumed that only the host evolved, but not the parasite. Variables including host population size, birth rates, death rates, and infection and recovery rates were factored into the model. The earlier study assumed that host birth rates would fluctuate due to the environment, but that they would do so symmetrically around a mean value, such that average birth rate would stay the same. The model predicted that seasonally stable environments would produce the most disease-resistant hosts.

This latest study adapted the earlier model to account for both host and parasite coevolution and experimentally tested those predictions in the lab. Again, the model assumed that average host birth rates would remain constant and predicted that stable environments would produce the most infectious phages and the most disease-resistant bacteria.

However, when Ferris tested these predictions in the lab, she found surprising results. First, she grew phage and bacteria together, allowing them to coevolve for several days in one kind of media. Then she transferred the pair into a nutritionally different media for another few days. Each pair underwent 24 such transfers between different media types. Some pairs always experienced nutritionally similar environments, mimicking mild seasonal change, while other pairs oscillated between very different nutritional environments. Control pairs experienced the same kind of media every time.

At the end of the transfer phase, bacteria from each pair were isolated and challenged to compete with phage from another pair. For example, Ferris pitted bacteria evolved in stable nutritional conditions against phage evolved in highly variable environments. She then assessed the level of resistance the bacteria had evolved and the level of infectivity the phage had evolved. Contrary to expectations, the phages that most effectively killed bacteria, and the bacteria that most effectively fought off phage, were those that had coevolved in moderately variable environments rather than in stable ones.

To understand why, Ferris turned back to her model and the initial assumption that average bacterial birth rates are constant even in variable environments. The experiments suggested otherwise. When Ferris updated her models to account for variable average birth rates, her predictions were much more similar to her experimental results.

Evolutionary ecologist Pedro Vale, a lecturer at the University of Edinburgh, Scotland, who was not involved in the study, praises the work’s combination of modeling and experimentation. “Even though coevolution is an intuitive idea, it’s incredibly difficult to show empirically,” he says. And it’s even more difficult, he adds, to show that it’s influenced by the added layer of environmental variation over time. The biggest contribution of this work, he says, is concretely demonstrating that environmental fluctuation does in fact change host–parasite coevolution.

Future studies could look beyond seasonal variation to study how other kinds of environmental variation also shape coevolution, notes coauthor Alex Best, a mathematician at the University of Sheffield and Ferris’ doctoral advisor. For example, many environments are spatially heterogeneous hosts and parasites may migrate between patches to escape or chase one another. Factoring in these migration dynamics, says Best, could improve future models.


Enzymatically active Rho and Rac small-GTPases are involved in the establishment of the vacuolar membrane after Toxoplasma gondii invasion of host cells

Background: GTPases are the family of hydrolases that bind and hydrolyze guanosine triphosphate. The large Immunity-related GTPases and the small GTPase ADP-ribosylation factor-6 in host cells are known to accumulate on the parasitophorous vacuole membrane (PVM) of Toxoplasma gondii and play critical roles in this parasite infection, but these GTPases cannot explain the full extent of infection.

Results: In this research, RhoA and Rac1 GTPases from the host cell were found to accumulate on the PVM regardless of the virulence of the T. gondii strains after T. gondii invasion, and this accumulation was dependent on their GTPase activity. The real-time micrography of T. gondii tachyzoites invading COS-7 cells overexpressing CFP-RhoA showed that this GTPase was recruited to the PVM at the very beginning of the invasion through the host cell membrane or from the cytosol. Host cell RhoA and Rac1 were also activated after T. gondii tachyzoites invasion, which was needed for host cell cytoskeleton reorganization to facilitate intracellular pathogens invasion. The decisive domains for the RhoA accumulation on the PVM included the GTP/Mg2+ binding site, the mDia effector interaction site, the G1 box, the G2 box and the G5 box, respectively, which were related to the binding of GTP for enzymatic activity and mDia for the regulation of microtubules. The recruited CFP-RhoA on the PVM could not be activated by epithelial growth factor (EGF) and no translocation was observed, unlike the unassociated RhoA in the host cell cytosol that migrated to the cell membrane towards the EGF activation spot. This result supported the hypothesis that the recruited RhoA or Rac1 on the PVM were in the GTP-bound active form. Wild-type RhoA or Rac1 overexpressed cells had almost the same infection rates by T. gondii as the mock-treated cells, while RhoA-N19 or Rac1-N17 transfected cells and RhoA, Rac1 or RhoA + Rac1 siRNA-treated cells showed significantly diminished infection rates compared to mock cells.

Conclusions: The accumulation of the RhoA and Rac1 on the PVM and the requisite of their normal GTPase activity for efficient invasion implied their involvement and function in T. gondii invasion.