Immune protection is dependent on the gut microbiome in a lethal mouse gammaherpesviral infection

Abstract

immunopathogenesis in systemic viral infections can induce a septic state with leaky capillary syndrome, disseminated coagulopathy, and high mortality with limited treatment options. Murine gammaherpesvirus-68 (MHV-68) intraperitoneal infection is a gammaherpesvirus model for producing severe vasculitis, colitis and lethal hemorrhagic pneumonia in interferon gamma receptor-deficient (IFNγR −/−) mice. In prior work, treatment with myxomavirus-derived Serp-1 or a derivative peptide S-7 (G 305 TTASSDTAITLIPR 319) induced immune protection, reduced disease severity and improved survival after MHV-68 infection. Here, we investigate the gut bacterial microbiome in MHV-68 infection. Antibiotic suppression markedly accelerated MHV-68 pathology causing pulmonary consolidation and hemorrhage, increased mortality and specific modification of gut microbiota. Serp-1 and S-7 reduced pulmonary pathology and detectable MHV-68 with increased CD3 and CD8 cells. Treatment efficacy was lost after antibiotic treatments with associated specific changes in the gut bacterial microbiota. In summary, transkingdom host-virus-microbiome interactions in gammaherpesvirus infection influences gammaherpesviral infection severity and reduces immune modulating therapeutic efficacy. Viral infections induce potent immune responses, an immunopathogenesis that can lead to severe complications with sepsis or leaky capillary syndromes and very high mortality and limited effective treatments, a true unmet clinical need. Sepsis has an associated risk of disseminated intravascular coagulation (DIC) with thrombosis, hemorrhage and shock 1-3. One such group of viruses with known severe complications are the gammaherpesviruses (GHV). The murine gammaherpesvirus-68 (MHV-68) is a widely used, well-controlled laboratory model of GHV host-pathogen interaction with genetic similarity to the human viruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) 4. Inflammatory vasculitic syndromes (IVS) are a group of rare, heterogeneous and devastating inflammatory conditions of the body's extensive system of blood vessels with increased morbidity, including sudden loss of vision, aneurysm, aortic arch syndrome, stroke, and associated increases in mortality 5-7. The etiology of many systemic vasculitides is currently unknown, with proposed mechanisms ranging from induction by fungal spores

Fibrinolytic Serine Proteases, Therapeutic Serpins and Inflammation: Fire Dancers and Firestorms

“…In more recent work, Serp-1 was found to be an effective therapeutic against severe vasculitis in both human temporal artery biopsy transplants from patients suspected to have Giant cell arteritis into SCID mice and in the lethal MHV68 gammaherpesvirus-induced vasculitis in interferon gamma receptor-deficient mice ( 162 , 209 ). Interestingly, peptides derived from Serp-1 are also therapeutically effective in the gammaherpesvirus-induced vasculitis model and protection imparted by both the full protein and the peptide derivatives are dependent on composition of the gut microbiome ( 202 , 210 , 211 ). In vitro studies demonstrated that, these reactive center loop (RCL) peptides bound and inhibited mammalian serpins ( 202 ).…”

Microbiota depletion promotes human rotavirus replication in an adult mouse model

“…The importance of the microbiota in establishing an appropriate anti-viral immune response has been noted [16,17]. Exacerbated systemic infection by several enteric and non-enteric viruses was observed in Ab-treated mice, including vesicular stomatitis and influenza virus [18], murine gammaherpesvirus [19], respiratory syncytial virus [20], encephalomyocarditis virus [21], and West Nile, Dengue and Zika viruses [22]. In some cases, microbiota depletion has been linked to a defective innate immune response characterized by low levels of type I IFN expression (IFNb), which hampered the ability to mount an effective antiviral macrophage response [18,20].…”

Low pathogenic avian influenza virus infection retards colon microbiome diversification in two different chicken lines

“…Those microorganisms undergo dynamic changes due to numerous factors, including ageing, changes in diet, environment, or infection by pathogens [28, 45–47]. Recent studies have shown that interaction between host microbiome and viruses may play a crucial role in dictating disease pathogenesis in mammalian hosts [24, 48, 49]. As in all vertebrates, chicken mucosal surfaces are share by diverse and dynamic population of microbiome [50–52].…”

“…Compelling evidence has shown that the gut microbiome can play a role in pathogenesis of various human diseases including those with primary involvement outside of the gut, such as respiratory, renal, or neurologic [20–22]. For instance, recent studies reveal that immune protection and severity of infection by gammaherpesvirus, which can cause severe vasculitis and lethal pneumonia or respiratory syncytial virus infection of the lungs, can be dependent on the profile of the human gut microbiome [23, 24].…”