Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract disease in children <2 years of age. Increased morbidity and mortality have been reported in high-risk patients, such as premature infants, patients with cardiac disease, and severely immune compromised patients. Severe disease is associated with the virulence of the virus as well as host factors specifically including the innate immune response. The role of type I interferons (IFNs) in the response to RSV infection is important in regulating the rate of virus clearance and in directing the character of the immune response, which is normally associated with protection and less severe disease. Two RSV non-structural proteins, NS1 and NS2, as well as the envelope G glycoprotein are known to suppress type I IFN production and a robust type I IFN response to RSV does not occur in human infants or neonatal mouse models of RSV infection. Additionally, presence of type I IFNs are associated with mild symptoms in infants and administration of IFN-α prior to infection of neonatal mice with RSV reduces immunopathology. This evidence has driven RSV prophylaxis and therapeutic efforts to consider strategies for enhancing type I IFN production.
Mosquito-borne viruses can cause severe inflammatory diseases and there are limited therapeutic solutions targeted specifically at virus-induced inflammation. Chikungunya virus (CHIKV), a re-emerging alphavirus responsible for several outbreaks worldwide in the past decade, causes debilitating joint inflammation and severe pain. Here, we show that CHIKV infection activates the NLRP3 inflammasome in humans and mice. Peripheral blood mononuclear cells isolated from CHIKV-infected patients showed elevated NLRP3, caspase-1 and interleukin-18 messenger RNA expression and, using a mouse model of CHIKV infection, we found that high NLRP3 expression was associated with peak inflammatory symptoms. Inhibition of NLRP3 activation using the small-molecule inhibitor MCC950 resulted in reduced CHIKV-induced inflammation and abrogated osteoclastogenic bone loss and myositis, but did not affect in vivo viral replication. Mice treated with MCC950 displayed lower expression levels of the cytokines interleukin-6, chemokine ligand 2 and tumour necrosis factor in joint tissue. Interestingly, MCC950 treatment abrogated disease signs in mice infected with a related arthritogenic alphavirus, Ross River virus, but not in mice infected with West Nile virus-a flavivirus. Here, using mouse models of alphavirus-induced musculoskeletal disease, we demonstrate that NLRP3 inhibition in vivo can reduce inflammatory pathology and that further development of therapeutic solutions targeting inflammasome function could help treat arboviral diseases.
Rationale: Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants worldwide. Although T-helper type 2 (Th2) cell pathology is implicated in severe disease, the mechanisms underlying the development of immunopathology are incompletely understood.Objectives: We aimed to identify local immune responses associated with severe RSV in infants. Our hypothesis was that disease severity would correlate with enhanced Th2 cellular responses.Methods: Nasal aspirates were collected from infants hospitalized with severe (admitted to the pediatric ICU) or moderate (maintained in the general ward) RSV disease at 5 to 9 days after enrollment. The immune response was investigated by evaluating T-lymphocyte cellularity, cytokine concentration, and viral load.Measurements and Main Results: Patients with severe disease had increased proportions of CD8 (cluster of differentiation 8)positive T cells expressing IL-4 (Tc2) and reduced proportions of CD8 1 T cells expressing IFNg (Tc1). Nasal aspirates from patients with severe disease had reduced concentrations of IL-17. Patients with greater frequencies of Tc1, CD8 1 T cells expressing IL-17 (Tc17), and CD4 1 T cells expressing IL-17 (Th17) had shorter durations of hospitalization.Conclusions: Severe RSV disease was associated with distinct T-cell profiles. Tc1, Tc17, and Th17 were associated with shorter hospital stay and may play a protective role, whereas Tc2 cells may play a previously underappreciated role in pathology.
Background: Respiratory syncytial virus (RSV) is the number one cause of lower respiratory tract infections in infants. There are still no vaccines or specific antiviral therapies against RSV, mainly due to the inadequate understanding of RSV pathogenesis. Recent data suggest a role for gut microbiota community structure in determining RSV disease severity. Our objective was to determine the gut microbial profile associated with severe RSV patients, which could be used to help identify at-risk patients and develop therapeutically protective microbial assemblages that may stimulate immuno-protection. Results: We enrolled 95 infants from Le Bonheur during the 2014 to 2016 RSV season. Of these, 37 were wellbabies and 58 were hospitalized with RSV. Of the RSV infected babies, 53 remained in the pediatric ward (moderate) and 5 were moved to the pediatric intensive care unit at a later date (severe). Stool samples were collected within 72 h of admission; and the composition of gut microbiota was evaluated via 16S sequencing of fecal DNA. There was a significant enrichment in S24_7, Clostridiales, Odoribacteraceae, Lactobacillaceae, and Actinomyces in RSV (moderate and severe) vs. controls. Patients with severe RSV disease had slightly lower alpha diversity (richness and evenness of the bacterial community) of the gut microbiota compared to patients with moderate RSV and healthy controls. Beta diversity (overall microbial composition) was significantly different between all RSV patients (moderate and severe) compared to controls and had significant microbial composition separating all three groups (control, moderate RSV, and severe RSV). Conclusions: Collectively, these data demonstrate that a unique gut microbial profile is associated with RSV disease and with severe RSV disease with admission to the pediatric intensive care unit. More mechanistic experiments are needed to determine whether the differences observed in gut microbiota are the cause or consequences of severe RSV disease.
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