Inflammation and Therapy for Respiratory Virus Infection

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Ongoing research focuses on the exploration of pathologic inflammatory responses to acute respiratory virus infection and the use of this information to develop creative strategies to circumvent the lethal sequelae characteristic of this disease. In FY2018, we contributed three (3) original research manuscripts on this topic as follows: Manuscript #1: Title: Alternaria alternata challenge at the nasal mucosa results in eosinophilic inflammation and increased susceptibility to influenza infection. Eosinophils in the nasal mucosa are an elemental feature of allergic rhinitis. Our original objective was to explore eosinophilic inflammation and its impact on respiratory virus infection at the nasal mucosa. Eosinophilic inflammation in the nasal mucosae of mice was established by repetitive stimulation with strict intranasal volumes of a filtrate of Alternaria alternata. Mice were then challenged with influenza virus (A/HK/1/68). Interestingly and unexpectedly, A. alternata-treated mice responded to an influenza virus infection with profound weight loss and mortality compared to mice that received diluent alone (0% vs 100% survival, ***p < .001); the lethal response was blunted when A. alternata was heat-inactivated. Minimal differences in virus titer were detected, and eosinophils present in the nasal passages at the time of virus inoculation provided no protection against the lethal sequelae of disease. Nasal wash fluids from mice treated with A. alternata included more neutrophils and higher levels of pro-inflammatory mediators in response to virus challenge, among these, IL 6, a biomarker for disease severity in human influenza. Critical point: Repetitive administration of A. alternata resulted in inflammation of the nasal mucosae and unanticipated morbidity and mortality in response to subsequent challenge with influenza A virus. Interestingly, and in contrast to findings in the lower airways, eosinophils recruited to the nasal passages provided no protection against lethal infection. However, as increased susceptibility to influenza virus among individuals with rhinitis has been the subject of several clinical reports, this model may be used for further exploration of these observations. Ref: M Ma, JL Redes, CM Percopo, KM Druey, HF Rosenberg. 2018. Clin. Exp. Allergy 48:691-702. Manuscript #2: Title: Regulator of G protein signaling 5 restricts neutrophil chemotaxis and trafficking. Neutrophils are white blood cells that are mobilized to damaged tissues and to sites of pathogen invasion, providing the first line of host defense. Here we show that Regulator of G protein signaling 5 (RGS5), a protein that modulates G protein activity, is expressed in both human and murine neutrophils. We detected significantly more neutrophils in the airways of Rgs5-/- mice than wild-type counterparts following acute respiratory virus infection with pneumonia virus of mice (PVM) a natural mouse pathogen that serves as a model of severe human RSV disease. Overall, our results indicate that RGS5 deficiency increases chemotaxis and adhesion, leading to more efficient neutrophil mobilization to inflamed tissues. These findings suggest that RGS5 expression and activity in neutrophils determine their migrational patterns in the complex microenvironments characteristic of inflamed tissues. Critical point: RGS5 is a critical modulator of neutrophil mobilization in a severe respiratory virus infection in vivo. Ref: EC Chan, C Ren, Z Xie, JA Jude, T Barker, CA Koziol-White, M Ma, RA Panettieri, D Wu, HF Rosenberg, KM Druey. 2018. J Biol Chem, in press Manuscript #3: Title: Osteoblasts Are Rapidly Ablated by Virus-Induced Systemic Inflammation following Lymphocytic Choriomeningitis Virus or Pneumonia Virus of Mice Infection in Mice. In this study, we provide evidence that infection of mice with either lymphocytic choriomeningitis virus (LCMV) or pneumonia virus of mice (PVM) resulted in rapid and substantial loss of osteoblasts from the bone surface. Osteoblast ablation was associated with elevated levels of circulating inflammatory cytokines, including TNF, IFN-gamma, IL-6, and CCL2. Both LCMV and PVM infections resulted in reduced osteoblast-specific gene expression in bone, loss of osteoblasts, and reduced serum markers of bone formation, including osteocalcin and procollagen type 1 N propeptide. Infection of Rag-1-deficient mice or specific depletion of CD8 T lymphocytes limited osteoblast loss associated with LCMV infection. By contrast, CD8 T cell depletion had no apparent impact on osteoblast ablation in association with PVM infection. Critical point: Virus infection and associated systemic inflammation lead to dramatic loss of osteoblasts. The clinical implications with respect to long-term bone loss and remodeling are worthy of further consideration. Ref: S Maltby, AJ Lochrin, B Bartlett, HL Tay, J Weaver, IJ Poulton, MW Plank, HF Rosenberg, NA Sims, PS Foster. 2018. J Immunol. 200:632-642.