scholarly journals Deciphering the Role of Leptospira Surface Protein LigA in Modulating the Host Innate Immune Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Ajay Kumar ◽  
Vivek P. Varma ◽  
Kavela Sridhar ◽  
Mohd Abdullah ◽  
Pallavi Vyas ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Modulation ◽  
Protein A ◽  
Adaptive Immune Response ◽  
Surface Protein ◽  
Variable Region ◽  
Nuclease Activity ◽  
Innate Immune ◽  
Surface Proteins

Leptospira, a zoonotic pathogen, is known to infect various hosts and can establish persistent infection. This remarkable ability of bacteria is attributed to its potential to modulate (activate or evade) the host immune response by exploiting its surface proteins. We have identified and characterized the domain of the variable region of Leptospira immunoglobulin-like protein A (LAV) involved in immune modulation. The 11th domain (A11) of the variable region of LigA (LAV) induces a strong TLR4 dependent innate response leading to subsequent induction of humoral and cellular immune responses in mice. A11 is also involved in acquiring complement regulator FH and binds to host protease Plasminogen (PLG), there by mediating functional activity to escape from complement-mediated killing. The deletion of A11 domain significantly impaired TLR4 signaling and subsequent reduction in the innate and adaptive immune response. It also inhibited the binding of FH and PLG thereby mediating killing of bacteria. Our study discovered an unprecedented role of LAV as a nuclease capable of degrading Neutrophil Extracellular Traps (NETs). This nuclease activity was primarily mediated by A11. These results highlighted the moonlighting function of LigA and demonstrated that a single domain of a surface protein is involved in modulating the host innate immune defenses, which might allow the persistence of Leptospira in different hosts for a long term without clearance.

scholarly journals Leptospira surface protein LigA plays a multifaceted role in modulating the host innate immune response

2020 ◽  
Author(s):  
Ajay Kumar ◽  
Vivek P. Varma ◽  
Kavela Sridhar ◽  
Mohd Abdullah ◽  
Pallavi Vyas ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Protein A ◽  
Surface Protein ◽  
Variable Region ◽  
Nuclease Activity ◽  
Innate Immune ◽  
Surface Proteins ◽  
Host Innate Immune Response ◽  
Complement Regulators

AbstractLeptospira, a zoonotic pathogen is known to infect a variety of hosts and capable of establishing persistent infection. This remarkable ability of bacteria is attributed to its potential to evade or modulate the host immune response by exploiting its surface proteins. We have identified and characterized the domain of Leptospira immunoglobulin-like protein A (LigA) that is involved in modulating the host innate immune response. We identified that the 11th domain (A11) of the variable region of LigA (LAV) induces strong TLR4 dependent innate response in mouse macrophages via signalling through MAP kinase pathway leading to the production of pro-inflammatory cytokines (IL-6 and TNF-α) and expression of costimulatory molecules (CD80, CD86, CD40) and maturation marker (MHC-II). A11 is also involved in acquiring complement regulators like FH, C4b binding protein and Plasminogen and mediating functional activity to escape from both classical and alternate pathways of complement-mediated killing. The deletion of A11 significantly impaired TLR4 signalling and subsequent activation of innate immune cells and also inhibited the binding of complement regulators leading to the killing of bacteria. Our study discovered an unprecedented role of LAV as nuclease capable of degrading Neutrophil Extracellular Traps (NETs). This nuclease activity was mediated by A11 and was inhibited with anti-LAV antibodies. These results highlight the moonlighting function of LigA and demonstrates that a single domain of a surface protein is involved in evading a myriad of host innate immune defences, which might allow the persistence of Leptospira in different hosts for a long term without clearance.

scholarly journals Screening of surface exposed lipoproteins of Leptospira involved in modulation of host innate immune response

2021 ◽  
Author(s):  
Ajay Kumar ◽  
Vivek P Varma ◽  
Syed M Faisal
Keyword(s):  
Immune Response ◽  
Immune Modulation ◽  
Acute Infection ◽  
Critical Role ◽  
Nuclease Activity ◽  
Innate Immune ◽  
Surface Proteins ◽  
Neutrophil Extracellular Trap ◽  
Plasmin Activity ◽  
Susceptible Host

Leptospira, a zoonotic pathogen is capable of causing both chronic and acute infection in susceptible host. Surface exposed lipoproteins play major role in modulating the host immune response by activating the innate cells like macrophages and DCs or evading complement attack and killing by phagocytes like neutrophils to favour pathogenesis and establish infection. In this study we screened some of surface exposed lipoproteins which are known to be involved in pathogenesis for their possible role in immune modulation (innate immune activation or evasion). Surface proteins of Len family (LenB, LenD, LenE), Lsa30, Loa22 and Lipl21 were purified in recombinant form and then tested for their ability to activate macrophages of different host (mouse, human and bovine). These proteins were tested for binding with complement regulators (FH, C4BP), host protease (plasminogen, PLG) and as nucleases to access their possible role in innate immune evasion. Our results show that of various proteins tested Loa22 induced strong innate activation and Lsa30 was least stimulatory as evident from production of pro-inflammatory cytokines (IL-6, TNF-a) and expression of surface markers (CD80, CD86, MHCII). All the tested proteins were able to bind to FH, C4BP and PLG, however Loa22 showed strong binding to PLG correlating to plasmin activity. All the proteins except Loa22 showed nuclease activity albeit with requirement of different metal ions. The nuclease activity of these proteins correlated to in vitro degradation of Neutrophil extracellular trap (NET). These results indicate that these surface proteins are involved in innate immune modulation and may play critical role in assisting the bacteria to invade and colonize the host tissue for persistent infection.

scholarly journals The Role of Semaphorins and Their Receptors in Innate Immune Responses and Clinical Diseases of Acute Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Shreya M. Kanth ◽  
Salina Gairhe ◽  
Parizad Torabi-Parizi
Keyword(s):  
Immune Response ◽  
Acute Inflammation ◽  
Neuronal Development ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
Acute Injury ◽  
Innate Immune Responses ◽  
Critical Function ◽  
Clinical Conditions

Semaphorins are a group of proteins that have been studied extensively for their critical function in neuronal development. They have been shown to regulate airway development, tumorigenesis, autoimmune diseases, and the adaptive immune response. Notably, emerging literature describes the role of immunoregulatory semaphorins and their receptors, plexins and neuropilins, as modulators of innate immunity and diseases defined by acute injury to the kidneys, abdomen, heart and lungs. In this review we discuss the pathogenic functions of semaphorins in clinical conditions of acute inflammation, including sepsis and acute lung injury, with a focus on regulation of the innate immune response as well as potential future therapeutic targeting.

scholarly journals Infection of Mice with Lyme Disease Spirochetes Constitutively Producing Outer Surface Proteins A and B

2007 ◽  
Vol 75 (6) ◽  
pp. 2786-2794 ◽  
Author(s):  
Keith O. Strother ◽  
Emir Hodzic ◽  
Stephen W. Barthold ◽  
Aravinda M. de Silva
Keyword(s):  
Immune Response ◽  
Lyme Disease ◽  
Outer Surface ◽  
Severe Disease ◽  
Protein A ◽  
Surface Protein ◽  
Surface Proteins ◽  
Mammalian Host ◽  
Outer Surface Protein A ◽  
Immunocompetent Mice

ABSTRACT Outer surface protein A (OspA) of the Lyme disease spirochete is primarily produced in the tick vector. OspA, which is a receptor for attaching spirochetes to the tick gut, is down regulated as the spirochetes leave the tick and enter the mammalian host. Although OspA is not a major antigen produced in the mammal, the protein appears to be produced under some conditions and production has been linked to more severe disease. A Lyme disease vaccine based on recombinant OspA has been approved for human use. However, the vaccine is no longer available, in part because of fears that OspA causes arthritis in people. To further understand the consequences of OspA production in the host, we created a Borrelia burgdorferi mutant that was unable to down regulate OspA. C3H/HeN mice infected with this mutant developed a specific anti-OspA immune response, and the spirochetes were unable to persist in these mice. In contrast, immunodeficient SCID mice were persistently infected with the mutant. We conclude that spirochetes producing OspA and B from the flaB promoter in immunocompetent mice stimulate an immune response that clear the bacteria without any signs of disease development in the mice.

The interaction of macrophage receptors with bacterial ligands

2006 ◽  
Vol 8 (28) ◽  
pp. 1-25 ◽  
Author(s):  
Annette Plüddemann ◽  
Subhankar Mukhopadhyay ◽  
Siamon Gordon
Keyword(s):  
Immune Response ◽  
Early Recognition ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
Surface Proteins ◽  
Scavenger Receptors ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Gram Negative ◽  
Macrophage Receptors

Innate immune receptors play a key role in the early recognition of invading bacterial pathogens and initiate the crucial innate immune response. The diverse macrophage receptors recognise Gram-positive and Gram-negative bacteria via conserved structures on the bacterial surface and facilitate phagocytosis and/or signalling, providing the trigger for the adaptive immune response. These receptors include scavenger receptors, C-type lectins, integrins, Toll-like receptors and siglecs. The bacterial ligands generally recognised by these receptors range from lipopolysaccharides on Gram-negative bacteria to peptidoglycan and lipoteichoic acid on Gram-positive bacteria. However, emerging evidence indicates that bacterial proteins are also important ligands; for example, surface proteins from Neisseria meningitidis have been shown to be ligands for class A scavenger receptors. In addition, a group of cytosolic receptors, the NBS-LRR proteins, have been implicated in recognition of bacterial breakdown products. It is becoming increasingly apparent that macrophage receptors can act in conjunction with one another to deliver an appropriate response.

scholarly journals Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 675
Author(s):  
Samira Elmanfi ◽  
Mustafa Yilmaz ◽  
Wilson W. S. Ong ◽  
Kofi S. Yeboah ◽  
Herman O. Sintim ◽  
...  
Keyword(s):  
Immune Response ◽  
Periodontal Disease ◽  
Innate Immune ◽  
Host Cells ◽  
Type I Interferons ◽  
Type I ◽  
Vaccine Adjuvants ◽  
Cyclic Dinucleotides ◽  
Sting Pathway

Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides—including c-di-GMP, c-di-AMP, and cGAMP—of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms “STING”, “TBK 1”, “IRF3”, and “cGAS”—alone, or together with “periodontitis”. Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.

Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis

Gut ◽  
2019 ◽  
Vol 68 (8) ◽  
pp. 1477-1492 ◽  
Author(s):  
Lijun Liao ◽  
Kai Markus Schneider ◽  
Eric J C Galvez ◽  
Mick Frissen ◽  
Hanns-Ulrich Marschall ◽  
...  
Keyword(s):  
Immune Response ◽  
Liver Injury ◽  
Sclerosing Cholangitis ◽  
Functional Role ◽  
Innate Immune ◽  
Caspase 8 ◽  
Inflammasome Activation ◽  
Intestinal Dysbiosis ◽  
Nlrp3 Inflammasome Activation

ObjectiveThere is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut–liver crosstalk for CLD in the murine Mdr2 knockout (Mdr2−/−) model resembling human primary sclerosing cholangitis (PSC).DesignMale Mdr2−/−, Mdr2−/− crossed with hepatocyte-specific deletion of caspase-8 (Mdr2−/−/Casp8∆hepa) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of Mdr2−/−-associated intestinal dysbiosis was studied by microbiota transfer experiments.ResultsMdr2−/− mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut–liver axis. Intestinal dysbiosis in Mdr2−/− mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of Mdr2−/− microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature.ConclusionsMDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.

scholarly journals Current Concepts of Biliary Atresia and Matrix Metalloproteinase-7: A Review of Literature

2020 ◽  
Vol 7 ◽  
Author(s):  
Mark Nomden ◽  
Leonie Beljaars ◽  
Henkjan J. Verkade ◽  
Jan B. F. Hulscher ◽  
Peter Olinga
Keyword(s):  
Immune Response ◽  
Liver Fibrosis ◽  
Pulmonary Fibrosis ◽  
Matrix Metalloproteinase ◽  
Biliary Atresia ◽  
Adaptive Immune Response ◽  
Cell Contact ◽  
T Helper 1 ◽  
Matrix Metalloproteinase 7

Biliary atresia (BA) is a rare cholangiopathy of infancy in which the bile ducts obliterate, leading to profound cholestasis and liver fibrosis. BA is hypothesized to be caused by a viral insult that leads to over-activation of the immune system. Patients with BA are surgically treated with a Kasai portoenterostomy (KPE), which aims to restore bile flow from the liver to the intestines. After KPE, progressive liver fibrosis is often observed in BA patients, even despite surgical success and clearance of their jaundice. The innate immune response is involved during the initial damage to the cholangiocytes and further differentiation of the adaptive immune response into a T-helper 1 cell (Th1) response. Multiple studies have shown that there is continuing elevation of involved cytokines that can lead to the progressive liver fibrosis. However, the mechanism by which the progressive injury occurs is not fully elucidated. Recently, matrix metalloproteinase-7 (MMP-7) has been investigated to be used as a biomarker to diagnose BA. MMPs are involved in extracellular matrix (ECM) turnover, but also have non-ECM related functions. The role of MMP-7 and other MMPs in liver fibrosis is just starting to be elucidated. Multiple studies have shown that serum MMP-7 measurements are able to accurately diagnose BA in a cohort of cholestatic patients while hepatic MMP-7 expression correlated with BA-related liver fibrosis. While the mechanism by which MMP-7 can be involved in the pathophysiology of BA is unclear, MMP-7 has been investigated in other fibrotic pathologies such as renal and idiopathic pulmonary fibrosis. MMP-7 is involved in Wnt/β-catenin signaling, reducing cell-to-cell contact by shedding of E-cadherin, amplifying inflammation and fibrosis via osteopontin (OPN) and TNF-α while it also appears to play a role in induction of angiogenesis This review aims to describe the current understandings of the pathophysiology of BA. Subsequently, we describe how MMP-7 is involved in other pathologies, such as renal and pulmonary fibrosis. Then, we propose how MMP-7 can potentially be involved in BA. By doing this, we aim to describe the putative role of MMP-7 as a prognostic biomarker in BA and to provide possible new therapeutic and research targets that can be investigated in the future.

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