Cross-Reactive Immunity Among Flaviviruses

Abstract

Flaviviruses consist of significant human pathogens responsible for hundreds of millions of infections each year. Their antigenic relationships generate immune responses that are cross-reactive to multiple flaviviruses and their widespread and overlapping geographical distributions, coupled with increases in vaccination coverage, increase the likelihood of exposure to multiple flaviviruses. Depending on the antigenic properties of the viruses to which a person is exposed, flavivirus cross-reactivity can be beneficial or could promote immune pathologies. In this review we describe our knowledge of the functional immune outcomes that arise from varied flaviviral immune statuses. The cross-reactive antibody and T cell immune responses that are protective versus pathological are also addressed.

Keywords: Zika; cross-protection; dengue; flavivirus; tick-borne encephalitis; vector-borne; yellow fever.

FIGURE 1

The antigenic relationships among flaviviruses. Phylogenetic analysis demonstrates that flaviviruses cluster not just antigenically but also group according to their known transmission vectors. Some of the most significant flaviviral human pathogens belong to the JEV, Spondweni, DENV, YFV, and mammalian TBV serocomplexes, respectively (arched lines cover viruses of the same serocomplex). Some of their most common vectors are also listed, such as the mosquito species Culex (blue) and Aedes (green) and various species of ticks (red). Other flaviviruses have no known vector, for example, viruses of the Modoc, Rio Bravo, and Entebbe bat virus complex (black). Among the Aedes mosquito-borne viruses of the YFV serocomplex, Saboya virus (pink) has been successfully isolated from the phlebotomine sand flies (85). Phylogenetic analysis was conducted using molecular evolutionary genetic analysis (MEGA-7) software (86). The full-length polyprotein amino acid sequences from various flaviviruses were obtained from the NCBI database and pairwise aligned using Clustal W. The phylogenetic tree was constructed by using the maximum likelihood method based on the Jones-Taylor-Thornton (JTT) matrix-based model (87). The consensus tree representing 200 bootstrap is presented (88). Branches that were reproduced in less than 50% bootstrap replicates are collapsed. The nodes show bootstrap support values from replicates.

FIGURE 2

Flavivirus cross-reactive cellular immune responses. Infection or vaccination against a flavivirus (Type-1) results in a primary immune response dominated by generation of Type-specific antibodies and T cell responses, followed by a memory formation. Owing to their antigenic relatedness, flavivirus cross-reactive antibodies and T cells (CD4 & CD8) are also generated. A secondary challenge with a second flavivirus (Type-2) can potentially reactivate cross-reactive memory T cells, those, which have higher specificity for Type-1 than for Type-2 flavivirus. These weakly cross-reactive memory T cells may outcompete naive T cells that would be more specific for Type-2, resulting in T cell original antigenic sin. However, memory T cells could also provide cross-protection directly by acquiring CTL function resulting in enhanced killing of virus-infected cells. Importantly cross-reactive CD4 Tfh cells can be recalled in the lymph node germinal centers, providing help to B cells, and improving both affinity and avidity of antibodies that are cross-reactive and neutralizing. Flavivirus cross-reactive antibodies also interact in different ways during a secondary flavivirus infection. After primary infection, high affinity and Type-specific antibodies are produced, which can neutralize virus when present at optimal concentrations. However, during secondary heterologous flavivirus infection, pre-existing cross-reactive, sub-neutralizing antibodies may lead to opsonization of virus particles and enhanced uptake by various immune cells such as monocytes via Fc receptors, resulting in increased virus replication, a phenomenon termed antibody-dependent enhancement (ADE).