Modulation of the Host Immune Response by Schistosome Egg-Secreted Proteins Is a Critical Avenue of Host–Parasite Communication

During a schistosome infection, the interactions that occur between the mammalian host and the parasite change rapidly once egg laying begins. Both juvenile and adult schistosomes adapt to indefinitely avoid the host immune system. In contrast, the survival of eggs relies on quickly traversing from the host. Following the commencement of egg laying, the host immune response undergoes a shift from a type 1 helper (Th1) inflammatory response to a type 2 helper (Th2) granulomatous response. This change is driven by immunomodulatory proteins within the egg excretory/secretory products (ESPs), which interact with host cells and alter their behaviour to promote egg translocation. However, in parallel, these ESPs also provoke the development of chronic schistosomiasis pathology. Recent studies using high-throughput proteomics have begun to characterise the components of schistosome egg ESPs, particularly those of Schistosoma mansoni, S. japonicum and S. haematobium. Future application of this knowledge may lead to the identification of proteins with novel immunomodulatory activity or pathological importance. However, efforts in this area are limited by a lack of in situ or in vivo functional characterisation of these proteins. This review will highlight the current knowledge of the content and demonstrated functions of schistosome egg ESPs.

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Leishmania donovani Secretory Mevalonate Kinase Regulates Host Immune Response and Facilitates Phagocytosis

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.641985 ◽

2021 ◽

Vol 11 ◽

Author(s):

Tanvir Bamra ◽

Taj Shafi ◽

Sushmita Das ◽

Manjay Kumar ◽

Manas Ranjan Dikhit ◽

...

Keyword(s):

Immune Response ◽

Immune System ◽

Leishmania Donovani ◽

Indian Subcontinent ◽

Parasite Burden ◽

Host Immune Response ◽

Host Cells ◽

Interleukin 4 ◽

Host Immune System ◽

Mevalonate Kinase

Summary StatementLeishmania secretes over 151 proteins during in vitro cultivation. Cellular functions of one such novel protein: mevalonate kinase is discussed here; signifying its importance in Leishmania infection.Visceral Leishmaniasis is a persistent infection, caused by Leishmania donovani in Indian subcontinent. This persistence is partly due to phagocytosis and evasion of host immune response. The underlying mechanism involves secretory proteins of Leishmania parasite; however, related studies are meagre. We have identified a novel secretory Leishmania donovani glycoprotein, Mevalonate kinase (MVK), and shown its importance in parasite internalization and immuno-modulation. In our studies, MVK was found to be secreted maximum after 1 h temperature stress at 37°C. Its secretion was increased by 6.5-fold in phagolysosome-like condition (pH ~5.5, 37°C) than at pH ~7.4 and 25°C. Treatment with MVK modulated host immune system by inducing interleukin-10 and interleukin-4 secretion, suppressing host’s ability to kill the parasite. Peripheral blood mononuclear cell (PBMC)-derived macrophages infected with mevalonate kinase-overexpressing parasites showed an increase in intracellular parasite burden in comparison to infection with vector control parasites. Mechanism behind the increase in phagocytosis and immunosuppression was found to be phosphorylation of mitogen-activated protein (MAP) kinase pathway protein, Extracellular signal-regulated kinases-1/2, and actin scaffold protein, cortactin. Thus, we conclude that Leishmania donovani Mevalonate kinase aids in parasite engulfment and subvert the immune system by interfering with signal transduction pathways in host cells, which causes suppression of the protective response and facilitates their persistence in the host. Our work elucidates the involvement of Leishmania in the process of phagocytosis which is thought to be dependent largely on macrophages and contributes towards better understanding of host pathogen interactions.

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Extracellular Vesicles in Viral Spread and Antiviral Response

Viruses ◽

10.3390/v12060623 ◽

2020 ◽

Vol 12 (6) ◽

pp. 623 ◽

Cited By ~ 5

Author(s):

Raquel Bello-Morales ◽

Inés Ripa ◽

José Antonio López-Guerrero

Keyword(s):

Immune Response ◽

Extracellular Vesicles ◽

Current Knowledge ◽

Host Immune Response ◽

Host Cells ◽

Viral Spread ◽

Viral Responses ◽

Hsv 1

Viral spread by both enveloped and non-enveloped viruses may be mediated by extracellular vesicles (EVs), including microvesicles (MVs) and exosomes. These secreted vesicles have been demonstrated to be an efficient mechanism that viruses can use to enter host cells, enhance spread or evade the host immune response. However, the complex interplay between viruses and EVs gives rise to antagonistic biological tasks—to benefit the viruses, enhancing infection and interfering with the immune system or to benefit the host, by mediating anti-viral responses. Exosomes from cells infected with herpes simplex type 1 (HSV-1) may transport viral and host transcripts, proteins and innate immune components. This virus may also use MVs to expand its tropism and evade the host immune response. This review aims to describe the current knowledge about EVs and their participation in viral infection, with a specific focus on the role of exosomes and MVs in herpesvirus infections, particularly that of HSV-1.

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The Bacterial Second Messenger Cyclic di-GMP Regulates Brucella Pathogenesis and Leads to Altered Host Immune Response

Infection and Immunity ◽

10.1128/iai.00531-16 ◽

2016 ◽

Vol 84 (12) ◽

pp. 3458-3470 ◽

Cited By ~ 11

Author(s):

Mike Khan ◽

Jerome S. Harms ◽

Fernanda M. Marim ◽

Leah Armon ◽

Cherisse L. Hall ◽

...

Keyword(s):

Immune Response ◽

Second Messenger ◽

Host Immune Response ◽

Vital Role ◽

Host Cells ◽

Content Type ◽

Type Iv

Brucella species are facultative intracellular bacteria that cause brucellosis, a chronic debilitating disease significantly impacting global health and prosperity. Much remains to be learned about how Brucella spp. succeed in sabotaging immune host cells and how Brucella spp. respond to environmental challenges. Multiple types of bacteria employ the prokaryotic second messenger cyclic di-GMP (c-di-GMP) to coordinate responses to shifting environments. To determine the role of c-di-GMP in Brucella physiology and in shaping host- Brucella interactions, we utilized c-di-GMP regulatory enzyme deletion mutants. Our results show that a Δ bpdA phosphodiesterase mutant producing excess c-di-GMP displays marked attenuation in vitro and in vivo during later infections. Although c-di-GMP is known to stimulate the innate sensor STING, surprisingly, the Δ bpdA mutant induced a weaker host immune response than did wild-type Brucella or the low-c-di-GMP guanylate cyclase Δ cgsB mutant. Proteomics analysis revealed that c-di-GMP regulates several processes critical for virulence, including cell wall and biofilm formation, nutrient acquisition, and the type IV secretion system. Finally, Δ bpdA mutants exhibited altered morphology and were hypersensitive to nutrient-limiting conditions. In summary, our results indicate a vital role for c-di-GMP in allowing Brucella to successfully navigate stressful and shifting environments to establish intracellular infection.

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Modulation of Host Immune Response Is an Alternative Strategy to Combat SARS-CoV-2 Pathogenesis

Frontiers in Immunology ◽

10.3389/fimmu.2021.660632 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lakhveer Singh ◽

Sakshi Bajaj ◽

Manoj Gadewar ◽

Nitin Verma ◽

Mohd Nazam Ansari ◽

...

Keyword(s):

Immune Response ◽

Life Cycle ◽

Immune System ◽

Host Immune Response ◽

Viral Rna ◽

Host Cells ◽

Spike Protein ◽

Host Immune System ◽

Host Membrane

The novel SARS-CoV-2virus that caused the disease COVID-19 is currently a pandemic worldwide. The virus requires an alveolar type-2 pneumocyte in the host to initiate its life cycle. The viral S1 spike protein helps in the attachment of the virus on toACE-2 receptors present on type-2 pneumocytes, and the S2 spike protein helps in the fusion of the viral membrane with the host membrane. Fusion of the SARS-CoV-2virus and host membrane is followed by entry of viral RNA into the host cells which is directly translated into the replicase-transcriptase complex (RTC) following viral RNA and structural protein syntheses. As the virus replicates within type-2 pneumocytes, the host immune system is activated and alveolar macrophages start secreting cytokines and chemokines, acting as an inflammatory mediator, and chemotactic neutrophils, monocytes, natural NK cells, and CD8+ T cells initiate the local phagocytosis of infected cells. It is not the virus that kills COVID-19 patients; instead, the aberrant host immune response kills them. Modifying the response from the host immune system could reduce the high mortality due to SARS-CoV-2 infection. The present study examines the viral life cycle intype-2 pneumocytes and resultant host immune response along with possible therapeutic targets.

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Glycomaterials for probing host–pathogen interactions and the immune response

Experimental Biology and Medicine ◽

10.1177/1535370216647811 ◽

2016 ◽

Vol 241 (10) ◽

pp. 1042-1053 ◽

Cited By ~ 3

Author(s):

Mia L Huang ◽

Christopher J Fisher ◽

Kamil Godula

Keyword(s):

Immune Response ◽

Immune System ◽

Cell Surface ◽

Host Response ◽

Host Immune Response ◽

Host Cells ◽

Host Immune System ◽

Host Pathogen Interactions ◽

Host Pathogen ◽

Functional Complexity

The initial engagement of host cells by pathogens is often mediated by glycan structures presented on the cell surface. Various components of the glycocalyx can be targeted by pathogens for adhesion to facilitate infection. Glycans also play integral roles in the modulation of the host immune response to infection. Therefore, understanding the parameters that define glycan interactions with both pathogens and the various components of the host immune system can aid in the development of strategies to prevent, interrupt, or manage infection. Glycomaterials provide a unique and powerful tool with which to interrogate the compositional and functional complexity of the glycocalyx. The objective of this review is to highlight some key contributions from this area of research in deciphering the mechanisms of pathogenesis and the associated host response.

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SUMO and SUMOylation Pathway at the Forefront of Host Immune Response

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.681057 ◽

2021 ◽

Vol 9 ◽

Author(s):

Sajeev T. K. ◽

Garima Joshi ◽

Pooja Arya ◽

Vibhuti Mahajan ◽

Akanksha Chaturvedi ◽

...

Keyword(s):

Immune Response ◽

Immune System ◽

Host Immune Response ◽

Defense Responses ◽

Effector Proteins ◽

Host Cells ◽

Host Immune System ◽

Target Proteins ◽

Adaptive Immune Cells ◽

Sumo Pathway

Pathogens pose a continuous challenge for the survival of the host species. In response to the pathogens, the host immune system mounts orchestrated defense responses initiating various mechanisms both at the cellular and molecular levels, including multiple post-translational modifications (PTMs) leading to the initiation of signaling pathways. The network of such pathways results in the recruitment of various innate immune components and cells at the site of infection and activation of the adaptive immune cells, which work in synergy to combat the pathogens. Ubiquitination is one of the most commonly used PTMs. Host cells utilize ubiquitination for both temporal and spatial regulation of immune response pathways. Over the last decade, ubiquitin family proteins, particularly small ubiquitin-related modifiers (SUMO), have been widely implicated in host immune response. SUMOs are ubiquitin-like (Ubl) proteins transiently conjugated to a wide variety of proteins through SUMOylation. SUMOs primarily exert their effect on target proteins by covalently modifying them. However, SUMO also engages in a non-covalent interaction with the SUMO-interacting motif (SIM) in target proteins. Unlike ubiquitination, SUMOylation alters localization, interactions, functions, or stability of target proteins. This review provides an overview of the interplay of SUMOylation and immune signaling and development pathways in general. Additionally, we discuss in detail the regulation exerted by covalent SUMO modifications of target proteins, and SIM mediated non-covalent interactions with several effector proteins. In addition, we provide a comprehensive review of the literature on the importance of the SUMO pathway in the development and maintenance of a robust immune system network of the host. We also summarize how pathogens modulate the host SUMO cycle to sustain infectability. Studies dealing mainly with SUMO pathway proteins in the immune system are still in infancy. We anticipate that the field will see a thorough and more directed analysis of the SUMO pathway in regulating different cells and pathways of the immune system. Our current understanding of the importance of the SUMO pathway in the immune system necessitates an urgent need to synthesize specific inhibitors, bioactive regulatory molecules, as novel therapeutic targets.

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Faster growth with shorter antigens explains a VSG hierarchy during African trypanosome infections: a feint attack by parasites

10.1101/131029 ◽

2017 ◽

Author(s):

Dianbo Liu ◽

Luca Albergante ◽

David Horn ◽

Timothy Newman

Keyword(s):

Immune Response ◽

Trypanosoma Brucei ◽

Temporal Distribution ◽

Inverse Correlation ◽

Host Immune Response ◽

Surface Proteins ◽

Host Immune System ◽

Differential Growth ◽

African Trypanosome

AbstractThe parasitic African trypanosome, Trypanosoma brucei, evades the adaptive host immune response by a process of antigenic variation that involves the clonal switching of variant surface glycoproteins (VSGs). The VSGs that periodically come to dominate in vivo display a hierarchy, but how this hierarchy arises is not well-understood. Combining publicly available genetic data with mathematical modelling, we report a VSG-length-dependent hierarchical timing of clonal VSG dominance in a mouse model, revealing an inverse correlation between VSG length and trypanosome growth-rate. Our analysis indicates that, among parasites switching to new VSGs, those expressing shorter VSGs preferentially accumulate to a detectable level that is sufficient to trigger an effective immune response. Subsequent elimination of faster-growing parasites then allows slower parasites with longer VSGs to accumulate. This interaction between the host and parasite is able by itself to explain the temporal distribution of VSGs observed in vivo. Thus, our findings reveal a length-dependent hierarchy that operates during T. brucei infection, representing a ‘feint attack’ diversion tactic utilised during infection by these persistent parasites to out-maneuver the host immune system.Significance StatementThe protozoan parasite Trypanosoma brucei causes devastating and lethal diseases in humans and livestock. This parasite continuously evades the host adaptive immune response by drawing on a library of variant surface proteins but the mechanisms determining the timing of surface protein – host interactions are not understood. We report a simple mechanism, based on differential growth of parasites with surface proteins of different lengths, which can explain the hierarchy of variants over time. This allows parasites to evade host immune responses for extended timeframes using limited cohorts of surface proteins. We liken this strategy to a military ‘feint attack’, that enhances the parasites ability to evade the host immune response. A similar mechanism may also operate in other important pathogens.

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The novel Dbl homology/BAR domain protein, MsgA, of Talaromyces marneffei regulates yeast morphogenesis during growth inside host cells

Scientific Reports ◽

10.1038/s41598-020-79593-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Harshini Weerasinghe ◽

Hayley E. Bugeja ◽

Alex Andrianopoulos

Keyword(s):

Pathogenic Fungi ◽

Host Cells ◽

Microbial Pathogens ◽

Mammalian Host ◽

Host Immune System ◽

Nucleotide Exchange ◽

Phagocytic Cells ◽

Macrophage Infection ◽

Bar Domain ◽

Talaromyces Marneffei

AbstractMicrobial pathogens have evolved many strategies to evade recognition by the host immune system, including the use of phagocytic cells as a niche within which to proliferate. Dimorphic pathogenic fungi employ an induced morphogenetic transition, switching from multicellular hyphae to unicellular yeast that are more compatible with intracellular growth. A switch to mammalian host body temperature (37 °C) is a key trigger for the dimorphic switch. This study describes a novel gene, msgA, from the dimorphic fungal pathogen Talaromyces marneffei that controls cell morphology in response to host cues rather than temperature. The msgA gene is upregulated during murine macrophage infection, and deletion results in aberrant yeast morphology solely during growth inside macrophages. MsgA contains a Dbl homology domain, and a Bin, Amphiphysin, Rvs (BAR) domain instead of a Plekstrin homology domain typically associated with guanine nucleotide exchange factors (GEFs). The BAR domain is crucial in maintaining yeast morphology and cellular localisation during infection. The data suggests that MsgA does not act as a canonical GEF during macrophage infection and identifies a temperature independent pathway in T. marneffei that controls intracellular yeast morphogenesis.

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Streptococcal Adhesion and Colonization

Critical Reviews in Oral Biology & Medicine ◽

10.1177/10454411970080020601 ◽

1997 ◽

Vol 8 (2) ◽

pp. 175-200 ◽

Cited By ~ 201

Author(s):

H.F. Jenkinson ◽

RJ Lamont

Keyword(s):

Immune Modulation ◽

Rational Design ◽

Repeated Sequence ◽

Host Cells ◽

Mammalian Host ◽

Related Factors ◽

Bacterial Populations ◽

Acellular Vaccines

Streptococci express arrays of adhesins on their cell surfaces that facilitate adherence to substrates present in their natural environment within the mammalian host. A consequence of such promiscuous binding ability is that streptococcal cells may adhere simultaneously to a spectrum of substrates, including salivary glycoproteins, extracellular matrix and serum components, host cells, and other microbial cells. The multiplicity of streptococcal adherence interactions accounts, at least in part, for their success in colonizing the oral and epithelial surfaces of humans. Adhesion facilitates colonization and may be a precursor to tissue invasion and immune modulation, events that presage the development of disease. Many of the streptococcal adhesins and virulence-related factors are cell-wall-associated proteins containing repeated sequence blocks of amino acids. Linear sequences, both within the blocks and within non-repetitive regions of the proteins, have been implicated in substrate binding. Sequences and functions of these proteins among the streptococci have become assorted through gene duplication and horizontal transfer between bacterial populations. Several adhesins identified and characterized through in vitro binding assays have been analyzed for in vivo expression and function by means of animal models used for colonization and virulence. Information on the molecular structure of adhesins as related to their in vivo function will allow for the rational design of novel acellular vaccines, recombinant antibodies, and adhesion agonists for the future control or prevention of streptococcal colonization and streptococcal diseases.

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Identification of Metabolically Quiescent Leishmania mexicana Parasites in Peripheral and Cured Dermal Granulomas Using Stable Isotope Tracing Imaging Mass Spectrometry

mBio ◽

10.1128/mbio.00129-21 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Joachim Kloehn ◽

Berin A. Boughton ◽

Eleanor C. Saunders ◽

Sean O’Callaghan ◽

Katrina J. Binger ◽

...

Keyword(s):

Mass Spectrometry ◽

Heavy Water ◽

Large Population ◽

Imaging Mass Spectrometry ◽

Host Cells ◽

Microbial Pathogens ◽

Mammalian Host ◽

Leishmania Mexicana ◽

First Line

ABSTRACT Leishmania are sandfly-transmitted protists that induce granulomatous lesions in their mammalian host. Although infected host cells in these tissues can exist in different activation states, the extent to which intracellular parasites stages also exist in different growth or physiological states remains poorly defined. Here, we have mapped the spatial distribution of metabolically quiescent and active subpopulations of Leishmania mexicana in dermal granulomas in susceptible BALB/c mice, using in vivo heavy water labeling and ultra high-resolution imaging mass spectrometry. Quantitation of the rate of turnover of parasite and host-specific lipids at high spatial resolution, suggested that the granuloma core comprised mixed populations of metabolically active and quiescent parasites. Unexpectedly, a significant population of metabolically quiescent parasites was also identified in the surrounding collagen-rich, dermal mesothelium. Mesothelium-like tissues harboring quiescent parasites progressively replaced macrophage-rich granuloma tissues following treatment with the first-line drug, miltefosine. In contrast to the granulomatous tissue, neither the mesothelium nor newly deposited tissue sequestered miltefosine. These studies suggest that the presence of quiescent parasites in acute granulomatous tissues, together with the lack of miltefosine accumulation in cured lesion tissue, may contribute to drug failure and nonsterile cure. IMPORTANCE Many microbial pathogens switch between different growth and physiological states in vivo in order to adapt to local nutrient levels and host microbicidal responses. Heterogeneity in microbial growth and metabolism may also contribute to nongenetic mechanisms of drug resistance and drug failure. In this study, we have developed a new approach for measuring spatial heterogeneity in microbial metabolism in vivo using a combination of heavy water (2H2O) labeling and imaging mass spectrometry. Using this approach, we show that lesions contain a patchwork of metabolically distinct parasite populations, while the underlying dermal tissues contain a large population of metabolically quiescent parasites. Quiescent parasites also dominate drug-depleted tissues in healed animals, providing an explanation for failure of some first line drugs to completely eradicate parasites. This approach is broadly applicable to study the metabolic and growth dynamics in other host-pathogen interactions.

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