The Adaptive Immune Response against Bunyavirales

Abstract

The Bunyavirales order includes at least fourteen families with diverse but related viruses, which are transmitted to vertebrate hosts by arthropod or rodent vectors. These viruses are responsible for an increasing number of outbreaks worldwide and represent a threat to public health. Infection in humans can be asymptomatic, or it may present with a range of conditions from a mild, febrile illness to severe hemorrhagic syndromes and/or neurological complications. There is a need to develop safe and effective vaccines, a process requiring better understanding of the adaptive immune responses involved during infection. This review highlights the most recent findings regarding T cell and antibody responses to the five Bunyavirales families with known human pathogens (Peribunyaviridae, Phenuiviridae, Hantaviridae, Nairoviridae, and Arenaviridae). Future studies that define and characterize mechanistic correlates of protection against Bunyavirales infections or disease will help inform the development of effective vaccines.

Keywords: Arenaviridae; Bunyavirales; Hantaviridae; Nairoviridae; Peribunyaviridae; Phenuiviridae; T cells; antibodies; bunyaviruses.

Figure 1

Bunyavirales virions and envelopes, infectious cycle, and antibody response. (A) Schematic representation of Peribunyaviridae, Phenuinviridae, Hantaviridae, Nairoviridae, and Arenaviridae envelope glycoproteins that enable virus entry into host cells. (B) Schematic representation of Bunyavirales infectious cycles, depicting viral RNA in the host cytoplasm initiating replication of infectious virus components. Newly synthesized glycoproteins of viruses within Peribunyaviridae, Phenuinviridae, Hantaviridae, and Nairoviridae form oligomers within the endoplasmic reticulum membrane and traffic to the Golgi apparatus for virion assembly and the subsequent budding of infectious particles. In contrast, Arenaviridae virions assemble at the cell membrane. (C) Schematic representation of neutralizing and non-neutralizing antibodies against Bunyavirales. Antibodies are known to target specific Bunyavirales proteins, typically Gc, Gn, and N, with each virus family having its own distinct major targets and neutralizing capabilities due to the viruses’ intricate nature. For the Peribunyaviridae family, nAbs mainly target Gc, whereas antibodies against N are generally less common and non-neutralizing. For Phenuinviridae, Gn is the main target for nAbs, with N and Gc proteins showing relatively less neutralization potential. For Hantaviridae, the most effective nAbs are against Gn and Gc. For Nairoviridae, Gc has been demonstrated as the primary target for the host nAbs, while other nNAbs directed at GP38 have been found to confer protection in rodent models. For Arenaviridae, different immunological patterns have been noted in response to Old and New World viruses. Typically, New World arenaviruses induce strong nAbs, while Old World arenaviruses often evade these responses. Glycoprotein structures were retrieved from PDB (Peribunyaviridae represented by La Crosse virus: 6H3W; Phenuiviridae represented by Rift Valley fever virus: 6F9F; Hantaviridae represented by Andes virus: 6ZJM; Nairovoridae represented by Crimean–Congo hemorrhagic fever virus: 8DC5; and, Arenaviridae represented by Lassa virus: 8EJH). nAb: neutralizing antibodies, nNAbs: non-neutralizing antibodies.

Figure 2

Vaccine design informed by studies on mechanistic correlates of immunity. (A) Vaccine design necessitates in-depth characterization of mechanistic correlates of immunity involving immunoinformatics analysis to help identify T cell and antibody targets, followed by ex vivo and in vivo characterization of adaptive immune responses during infection and/or vaccination. (B) Design of vaccine candidates should be tailored towards preventing or treating infections by specific viruses, with a long-term goal of potentially developing and testing cross-protective Bunyavirales vaccines. (C) Various delivery modalities can be employed for vaccine candidates including traditional approaches like inactivated/live attenuated viruses or protein-based vaccines, or more novel methods such as mRNA vaccines or monoclonal antibody therapies.