Immunopathogenic insights into members of the class Bunyaviricetes: a comparative review of emerging zoonotic threats

The class Bunyaviricetes encompasses a diverse group of vector- and rodent-borne viruses, many of which are major human pathogens causing severe and often lethal diseases worldwide. These include Lassa fever virus ( Arenaviridae ), hantaviruses such as Hantaan and Andes viruses ( Hantaviridae ), Crimean-Congo hemorrhagic fever virus ( Nairoviridae ), La Crosse and Oropouche viruses ( Peribunyaviridae ), and Rift Valley fever, severe fever with thrombocytopenia syndrome, and Toscana viruses ( Phenuiviridae ). Clinical syndromes range from hemorrhagic fever with multiorgan failure, vascular leak, and shock to acute encephalitis and severe respiratory distress. Despite their public health impact, safe and effective vaccines or targeted therapeutics are lacking for most bunyaviricetes diseases, leaving supportive care as the primary intervention. This review provides a comparative analysis of the immunopathogenesis of major human-pathogenic bunyaviricetes, highlighting shared and virus-specific strategies for innate immune evasion, cytokine modulation, and host cell targeting. Severe disease often arises from viral interference with key sensing pathways, such as RIG-I/MDA5 and downstream IRF and NF-κB signaling, which either suppresses interferon responses or leads to dysregulated inflammation. By integrating molecular, immunological, and clinical insights, we outline how these immune-virus interactions shape disease trajectory and severity. Understanding these mechanisms is critical for guiding the rational design of vaccines, antivirals, and immunomodulatory therapies, and for strengthening preparedness against these persistent zoonotic threats.