Repurposing of drugs targeting the cytokine storm induced by SARS-CoV-2.

A cytokine storm is one of the leading causes of acute respiratory distress syndrome (ARDS) and sepsis-associated multiple organ failure in many respiratory viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The coronavirus disease 2019 (COVID-19) pandemic has caused millions of deaths worldwide, resulting in an urgent need for effective therapeutic interventions. Repurposing immunosuppressive drugs that target cytokines with immunomodulatory properties is a promising approach to counteract SARS-CoV-2-induced ARDS at the infective and post-infective stages. In this minireview, we examine drugs targeting IL-1ß, IL-4/IL-13, IL-6 and TNF-α tested in COVID-19 patients.

Interleukin-17 Contributes to Chikungunya Virus-Induced Disease.

Alphaviral arthritides caused by mosquito-borne arboviruses such as chikungunya virus (CHIKV) can persist for months after the initial acute disease. Here, we investigated the contribution of interleukin-17 (IL-17), a cytokine involved in chronic autoimmune arthropathies such as rheumatoid arthritis, to the development of alphaviral arthropathy. Sera from CHIKV-infected patients who displayed both acute and chronic disease showed high levels of IL-17, IL-6, IL-21, IL-22, and IL-23, especially during the chronic phase of disease. We sought to validate these findings using a mouse model of CHIKV infection and disease using wild-type and IL-17A-deficient mice. Mice were infected with CHIKV, and joint and muscle tissues were harvested at designated time points. Tissue infiltrates were examined by immunohistochemistry, and tissue mRNA and protein expression of cytokines was assessed. Joint and muscle pathology was assessed using histology. CHIKV-infected mice lacking IL-17A showed reduced tissue inflammation and neutrophil infiltration, compared to wild-type mice. These investigations showed a role for IL-17 in the acute phase of CHIKV infection and also during the postacute disease resolution phase. IMPORTANCE CHIKV has been prevalent in Africa, Asia, and the Indian Ocean Islands for decades. There are currently no clinically approved vaccines or specific antiviral drugs targeting CHIKV. The upregulation of IL-17 detected in CHIKV disease patients and the reduced disease seen in IL-17-deficient mice suggest a correlation between IL-17 signaling pathways and CHIKV-induced arthritic inflammation. With an established role in contributing to the pathogenesis of immune-mediated diseases, such as psoriatic arthritis and rheumatoid arthritis, IL-17 signaling plays an important role in alphavirus arthritides.

TIR-Domain-Containing Adapter-Inducing Interferon-ß (TRIF)-Dependent Antiviral Responses Protect Mice against Ross River Virus Disease.

Ross River virus (RRV) is the major mosquito-borne virus in the South Pacific region. RRV infections are characterized by arthritic symptoms, which can last from several weeks to months. Type I interferon (IFN), the primary antiviral innate immune response, is able to modulate adaptive immune responses. The relationship between the protective role of type I IFN and the induction of signaling proteins that drive RRV disease pathogenesis remains poorly understood. In the present study, the role of TIR-domain-containing adapter-inducing interferon-ß (TRIF), an essential signaling adaptor protein downstream of Toll-like receptor (TLR) 3, a key single-stranded RNA (ssRNA)-sensing receptor, was investigated. We found that TRIF-/- mice were highly susceptible to RRV infection, with severe disease, high viremia, and a low type I IFN response early during disease development, which suggests the TLR3-TRIF axis may engage early in response to RRV infection. The number and the activation level of CD4+ T cells, CD8+ T cells, and NK cells were reduced in TRIF-/- mice compared to those in infected wild-type (WT) mice. In addition, the number of germinal center B cells was lower in TRIF-/- mice than WT mice following RRV infection, with lower titers of IgG antibodies detected in infected TRIF-/- mice compared to WT. Interestingly, the requirement for TRIF to promote immunoglobulin class switch recombination was at the level of the local immune microenvironment rather than B cells themselves. The slower resolution of RRV disease in TRIF-/- mice was associated with persistence of the RRV genome in muscle tissue and a continuing IFN response. IMPORTANCE RRV has been prevalent in the South Pacific region for decades and causes substantial economic and social costs. Though RRV is geographically restricted, a number of other alphaviruses have spread globally due to expansion of the mosquito vectors and increased international travel. Since over 30 species of mosquitoes have been implicated as potent vectors for RRV dissemination, RRV has the potential to further expand its distribution. In the pathogenesis of RRV disease, it is still not clear how innate immune responses synergize with adaptive immune responses. Type I IFN is crucial for bridging innate to adaptive immune responses to viral invasion. Hence, key signaling proteins in type I IFN induction pathways, which are important for type I IFN modulation, may also play critical roles in viral pathogenesis. This study provides insight into the role of TRIF in RRV disease development.