Immune Dysregulation in Arboviral Infections: Dengue, Zika, and Chikungunya – A Review Paper

Abstract

Arboviral infections, particularly dengue virus (DENV), Zika virus (ZIKV), and chikungunya virus (CHIKV), represent a major and growing global public health challenge, with a disproportionate burden in tropical and subtropical regions [1–3]. These positive-sense single-stranded RNA viruses, primarily transmitted by Aedes aegypti and Aedes albopictus mosquitoes, are responsible for recurrent epidemics affecting millions of individuals annually [2,4].
A central determinant of disease severity in these infections is immune dysregulation, arising from a complex interplay between viral factors and host immune responses [5,6]. Following infection, innate immune recognition via pattern recognition receptors such as Toll-like receptors and RIG-I-like receptors initiates antiviral defenses, including type I interferon responses and pro-inflammatory cytokine production [7,8]. However, many arboviruses have evolved mechanisms to evade or subvert these pathways, leading to delayed or impaired antiviral responses [9]. This dysregulation is further amplified during the adaptive immune phase, where aberrant T-cell activation, skewed cytokine profiles, and dysfunctional B-cell responses contribute to immunopathology [10].
In dengue infection, antibody-dependent enhancement (ADE) remains a hallmark mechanism, whereby pre-existing non-neutralizing antibodies facilitate viral entry into Fc receptor-bearing cells, resulting in increased viral replication and heightened inflammatory responses [11,12]. This is often accompanied by a cytokine storm characterized by elevated levels of TNF-α, IL-6, IL-10, and other mediators that promote vascular permeability and plasma leakage [13,14]. In contrast, Zika virus infection is associated with relatively attenuated early immune responses but pronounced neurotropism, with immune-mediated damage contributing to severe neurological outcomes such as microcephaly and Guillain–Barré syndrome [15,16]. Chikungunya virus infection is distinguished by robust and persistent inflammatory responses, particularly involving monocytes and macrophages, which underlie the development of chronic arthralgia and long-term joint pathology [17].

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