Chikungunya disease (CHIKD) is a viral infection caused by an alphavirus, chikungunya virus (CHIKV), and triggers large outbreaks leading to epidemics. Despite the low mortality rate, it is a major public health concern owing to high morbidity in affected individuals. The complete spectrum of this disease can be divided into four phases based on its clinical presentation and immunopathology. When a susceptible individual is bitten by an infected mosquito, the bite triggers inflammatory responses attracting neutrophils and initiating a cascade of events, resulting in the entry of the virus into permissive cells. This phase is termed the pre-acute or the intrinsic incubation phase. The virus utilizes the cellular components of the innate immune system to enter into circulation and reach primary sites of infection such as the lymph nodes, spleen, and liver. Also, at this point, antigen-presenting cells (APCs) present the viral antigens to the T cells thereby activating and initiating adaptive immune responses. This phase is marked by the exhibition of clinical symptoms such as fever, rashes, arthralgia, and myalgia and is termed the acute phase of the disease. Viremia reaches its peak during this phase, thereby enhancing the antigen-specific host immune response. Simultaneously, T cell-mediated activation of B cells leads to the formation of CHIKV specific antibodies. Increase in titres of neutralizing IgG/IgM antibodies results in the clearance of virus from the bloodstream and marks the initiation of the post-acute phase. Immune responses mounted during this phase of the infection determine the degree of disease progression or its resolution. Some patients may progress to a chronic arthritic phase of the disease that may last from a few months to several years, owing to a compromised disease resolution. The present review discusses the immunopathology of CHIKD and the factors that dictate disease progression and its resolution.
The Chikungunya virus (CHIKV) is a re-emerging arbovirus, in which its infection causes a febrile illness also commonly associated with severe joint pain and myalgia. Although the immune response to CHIKV has been studied, a better understanding of the virus-host interaction mechanisms may lead to more effective therapeutic interventions. In this context, neutrophil extracellular traps (NETs) have been described as a key mediator involved in the control of many pathogens, including several bacteria and viruses, but no reports of this important protective mechanism were documented during CHIKV infection. Here we demonstrate that the experimental infection of mouse-isolated neutrophils with CHIKV resulted in NETosis (NETs release) through a mechanism dependent on TLR7 activation and reactive oxygen species generation. In vitro, mouse-isolated neutrophils stimulated with phorbol 12-myristate 13-acetate release NETs that once incubated with CHIKV, resulting in further virus capture and neutralization. In vivo, NETs inhibition by the treatment of the mice with DNase resulted in the enhanced susceptibility of IFNAR−/− mice to CHIKV experimental acute infection. Lastly, by accessing the levels of MPO-DNA complex on the acutely CHIKV-infected patients, we found a correlation between the levels of NETs and the viral load in the blood, suggesting that NETs are also released in natural human infection cases. Altogether our findings characterize NETosis as a contributing natural process to control CHIKV acute infection, presenting an antiviral effect that helps to control systemic virus levels.
Frontiers in Immunology
Exploring Antiviral Immune Responses and Therapeutic Strategies Against Human Coronaviruses