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

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

Pathogens ◽

10.3390/pathogens10070863 ◽

2021 ◽

Vol 10 (7) ◽

pp. 863

Author(s):

Jack P. Carson ◽

Geoffrey N. Gobert

Keyword(s):

Immune Response ◽

Current Knowledge ◽

Host Immune Response ◽

Egg Laying ◽

Host Cells ◽

Future Application ◽

Mammalian Host ◽

Immunomodulatory Activity ◽

Host Immune System

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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Cryptococcus neoformans Rim101 Is Associated with Cell Wall Remodeling and Evasion of the Host Immune Responses

mBio ◽

10.1128/mbio.00522-12 ◽

2013 ◽

Vol 4 (1) ◽

Cited By ~ 55

Author(s):

Teresa R. O'Meara ◽

Stephanie M. Holmer ◽

Kyla Selvig ◽

Fred Dietrich ◽

J. Andrew Alspaugh

Keyword(s):

Immune Response ◽

Cell Wall ◽

Transcription Factor ◽

Immune System ◽

Immune Responses ◽

Cryptococcus Neoformans ◽

Host Immune Response ◽

Host Immune System ◽

Content Type ◽

Host Pathogen

ABSTRACTInfectious microorganisms often play a role in modulating the immune responses of their infected hosts. We demonstrate thatCryptococcus neoformanssignals through the Rim101 transcription factor to regulate cell wall composition and the host-pathogen interface. In the absence of Rim101,C. neoformansexhibits an altered cell surface in response to host signals, generating an excessive and ineffective immune response that results in accelerated host death. This host immune response to therim101Δ mutant strain is characterized by increased neutrophil influx into the infected lungs and an altered pattern of host cytokine expression compared to the response to wild-type cryptococcal infection. To identify genes associated with the observed phenotypes, we performed whole-genome RNA sequencing experiments under capsule-inducing conditions. We defined the downstream regulon of the Rim101 transcription factor and determined potential cell wall processes involved in the capsule attachment defects and altered mechanisms of virulence in therim101Δ mutant. The cell wall generates structural stability for the cell and allows the attachment of surface molecules such as capsule polysaccharides. In turn, the capsule provides an effective mask for the immunogenic cell wall, shielding it from recognition by the host immune system.IMPORTANCECryptococcus neoformansis an opportunistic human pathogen that is a significant cause of death in immunocompromised individuals. There are two major causes of death due to this pathogen: meningitis due to uncontrolled fungal proliferation in the brain in the face of a weakened immune system and immune reconstitution inflammatory syndrome characterized by an overactive immune response to subclinical levels of the pathogen. In this study, we examined howC. neoformansuses the conserved Rim101 transcription factor to specifically remodel the host-pathogen interface, thus regulating the host immune response. These studies explored the complex ways in which successful microbial pathogens induce phenotypes that ensure their own survival while simultaneously controlling the nature and degree of the associated host response.

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Two-hit Hypothesis and Multiple Organ Dysfunction Syndrome

Journal of Nepal Medical Association ◽

10.31729/jnma.318 ◽

2008 ◽

Vol 47 (170) ◽

Cited By ~ 2

Author(s):

I Butt ◽

Badri Man Shrestha

Keyword(s):

Immune Response ◽

Intensive Care ◽

Immune System ◽

Organ Dysfunction ◽

Multiple Organ Dysfunction Syndrome ◽

Host Immune Response ◽

Multiple Organ ◽

Severe Injury ◽

Host Immune System ◽

Multiple Organ Dysfunction

A severe insult in the form of infection or trauma primes the host immune system so that a subsequent,relatively trivial insult produces a markedly exaggerated host immune response, which can leadto multiple organ dysfunction syndrome (MODS) and death. This forms the basis of the “two-hithypothesis” (THH), which is being increasingly recognised as an important cause of morbidity andmortality following severe injury and sepsis, particularly in intensive care settings. Appreciation ofthe impact ofrepeatedinsults andpathophysiology of MODS is vital in the prevention of this seriouscomplication. We describe a case which illustrates the concept of THH and MODS and present areview of literature on this subject.Key words: laparotomy, multiple organ dysfunction, sepsis, two-hit hypothesis

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Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection

10.21203/rs.3.rs-235742/v1 ◽

2021 ◽

Author(s):

Zhuo Zhou ◽

Xinyi Zhang ◽

Xiaobo Lei ◽

Xia Xiao ◽

Tao Jiao ◽

...

Keyword(s):

Immune Response ◽

Immune System ◽

Cell Fusion ◽

Innate Immune Response ◽

Rna Virus ◽

Cellular Level ◽

Innate Immune ◽

Host Cells ◽

Host Immune System ◽

Sting Pathway

Abstract The global coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense RNA virus. How the host immune system senses and responds to SARS-CoV-2 infection remain to be determined. Here, we report that SARS-CoV-2 infection activates the innate immune response through the cytosolic DNA sensing cGAS-STING pathway. SARS-CoV-2 infection induces the cellular level of 2'3'-cGAMP associated with STING activation. cGAS recognizes chromatin DNA shuttled from the nucleus as a result of cell-to-cell fusion upon SARS-CoV-2 infection. We further demonstrate that the expression of spike protein from SARS-CoV-2 and ACE2 from host cells is sufficient to trigger cytoplasmic chromatin upon cell fusion. Furthermore, cytoplasmic chromatin-cGAS-STING pathway, but not MAVS mediated viral RNA sensing pathway, contributes to interferon and pro-inflammatory gene expression upon cell fusion. Finally, we show that cGAS is required for host antiviral responses against SARS-CoV-2, and a STING-activating compound potently inhibits viral replication. Together, our study reported a previously unappreciated mechanism by which the host innate immune system responds to SARS-CoV-2 infection, mediated by cytoplasmic chromatin from the infected cells. Targeting the cytoplasmic chromatin-cGAS-STING pathway may offer novel therapeutic opportunities in treating COVID-19. In addition, these findings extend our knowledge in host defense against viral infection by showing that host cells’ self-nucleic acids can be employed as a “danger signal” to alarm the immune system.

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Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00800-3 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Zhuo Zhou ◽

Xinyi Zhang ◽

Xiaobo Lei ◽

Xia Xiao ◽

Tao Jiao ◽

...

Keyword(s):

Immune Response ◽

Immune System ◽

Cell Fusion ◽

Innate Immune Response ◽

Rna Virus ◽

Cellular Level ◽

Innate Immune ◽

Host Cells ◽

Host Immune System ◽

Sting Pathway

AbstractThe global coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense RNA virus. How the host immune system senses and responds to SARS-CoV-2 infection remain largely unresolved. Here, we report that SARS-CoV-2 infection activates the innate immune response through the cytosolic DNA sensing cGAS-STING pathway. SARS-CoV-2 infection induces the cellular level of 2′3′-cGAMP associated with STING activation. cGAS recognizes chromatin DNA shuttled from the nucleus as a result of cell-to-cell fusion upon SARS-CoV-2 infection. We further demonstrate that the expression of spike protein from SARS-CoV-2 and ACE2 from host cells is sufficient to trigger cytoplasmic chromatin upon cell fusion. Furthermore, cytoplasmic chromatin-cGAS-STING pathway, but not MAVS-mediated viral RNA sensing pathway, contributes to interferon and pro-inflammatory gene expression upon cell fusion. Finally, we show that cGAS is required for host antiviral responses against SARS-CoV-2, and a STING-activating compound potently inhibits viral replication. Together, our study reported a previously unappreciated mechanism by which the host innate immune system responds to SARS-CoV-2 infection, mediated by cytoplasmic chromatin from the infected cells. Targeting the cytoplasmic chromatin-cGAS-STING pathway may offer novel therapeutic opportunities in treating COVID-19. In addition, these findings extend our knowledge in host defense against viral infection by showing that host cells’ self-nucleic acids can be employed as a “danger signal” to alarm the immune system.

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How the insect immune system interacts with an obligate symbiotic bacterium

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2010.1563 ◽

2010 ◽

Vol 278 (1704) ◽

pp. 333-338 ◽

Cited By ~ 40

Author(s):

A. E. Douglas ◽

S. Bouvaine ◽

R. R. Russell

Keyword(s):

Immune Response ◽

Immune System ◽

Acyrthosiphon Pisum ◽

Gene Expression Pattern ◽

Symbiotic Bacterium ◽

Host Cells ◽

Host Immune System ◽

S2 Cells ◽

Microbial Infection ◽

Imd Pathway

The animal immune system provides defence against microbial infection, and the evolution of certain animal–microbial symbioses is predicted to involve adaptive changes in the host immune system to accommodate the microbial partner. For example, the reduced humoral immune system in the pea aphid Acyrthosiphon pisum , including an apparently non-functional immune deficiency (IMD) signalling pathway and absence of peptidoglycan recognition proteins (PGRPs), has been suggested to be an adaptation for the symbiosis with the bacterium Buchnera aphidicola . To investigate this hypothesis, the interaction between Buchnera and non-host cells, specifically cultured Drosophila S2 cells, was investigated. Microarray analysis of the gene expression pattern in S2 cells indicated that Buchnera triggered an immune response, including upregulated expression of genes for antimicrobial peptides via the IMD pathway with the PGRP-LC as receptor. Buchnera cells were readily taken up by S2 cells, but were subsequently eliminated over 1–2 days. These data suggest that Buchnera induces in non-host cells a defensive immune response that is deficient in its host. They support the proposed contribution of the Buchnera symbiosis to the evolution of the apparently reduced immune function in the aphid host.

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Protective microbe enhances colonisation of a novel host species by modifying immune gene expression

10.1101/857540 ◽

2019 ◽

Author(s):

Suzanne A. Ford ◽

Kayla C. King

Keyword(s):

Gene Expression ◽

Staphylococcus Aureus ◽

Immune Response ◽

Immune System ◽

Host Species ◽

Gene Families ◽

Host Immune Response ◽

Host Immune System ◽

Immune Gene ◽

New Host

AbstractMicrobes that protect against infection inhabit hosts across the tree of life. It is unclear whether many protective microbes use or reduce the need for a host immune response, or how the immune system reacts when these microbes newly encounter a host species naturally and as part of a biocontrol strategy. We sequenced the transcriptome of a host (Caenorhabditis elegans) following its interaction with a non-native bacterium (Enterococcus faecalis) that has protective traits against the pathogen, Staphylococcus aureus. We show that microbe-mediated protection caused the differential expression of 1,557 genes, including the upregulation of many immune gene families conserved across the animal kingdom (e.g. lysozymes and c-type lectins). We found that this modulation of the host’s immune response was beneficial for both the protective microbe and the host. Given E. faecalis’ increased ability to resist lysozyme activity compared to S. aureus, our results indicate that the protective microbe could more easily invade and protect infected hosts by upregulating lysozyme genes. These results suggest that a protective microbe can exploit the host immune system even when introduced into a novel species. Microbes that protect via the host immune response in this way should favour continued investment into host immunity and avoid the evolution of host dependence.Author summaryOrganisms can be protected from infectious disease by the microbes they house. It is unclear, however, whether protective microbes affect the host immune response to infection, particularly in the early stages of symbiosis. In this study, we investigated the role of the host immune system in a novel protective interaction. We examined gene expression in a nematode after colonisation by a non-native microbe capable of suppressing the pathogen Staphylococcus aureus. The protective microbe altered the host immune response to infection in a way that it could exploit. By causing the host to increase the production of antimicrobials to which it itself is relatively resistant, the protective microbe was better able to colonise and defend infected hosts. These results indicate that protective microbes introduced into new host species can take advantage of the host immune system. Such a mechanism at the beginning of a protective symbiosis, formed either naturally or as part of a biocontrol strategy, could ensure continued investment in host-based defences over evolutionary time.

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