T-Cell Response to Viral Hemorrhagic Fevers

Abstract

Viral hemorrhagic fevers (VHF) are a group of clinically similar diseases that can be caused by enveloped RNA viruses primarily from the families Arenaviridae, Filoviridae, Hantaviridae, and Flaviviridae. Clinically, this group of diseases has in common fever, fatigue, dizziness, muscle aches, and other associated symptoms that can progress to vascular leakage, bleeding and multi-organ failure. Most of these viruses are zoonotic causing asymptomatic infections in the primary host, but in human beings, the infection can be lethal. Clinical and experimental evidence suggest that the T-cell response is needed for protection against VHF, but can also cause damage to the host, and play an important role in disease pathogenesis. Here, we present a review of the T-cell immune responses to VHF and insights into the possible ways to improve counter-measures for these viral agents.

Keywords: Ebola virus; Lassa virus; T-cells; dengue virus; hantavirus; interferon-gamma; tumor necrosis factor-alpha; vaccine; viral hemorrhagic fever; yellow fever virus.

Figure 1

Common characteristics of viral hemorrhagic fever and the induced T-cell response. Lassa virus (LASV), ebola virus (EBOV), Hantaan virus (HNTV), and dengue virus (DENV), which share some virologic and epidemiological characteristics, primarily target dendritic cells and monocytes/macrophages during early infection, and induce three types of T-cell responses: 1. A low expression of costimulatory molecules (CD80/CD86), cytokine production and/or presentation of non-dominant epitopes, induces a poor T-cell activation, with low proliferation, low interferon (IFN)-γ and tumor necrosis factor (TNF)-α production and reduced cytotoxic potential. These defects can be responsible for severe disease/death, low induction of neutralizing antibodies, poor immunological memory and increased susceptibility to coinfections. 2. An efficient costimulation, cytokine production, and presentation of relevant epitopes under the context of protective HLA alleles, leads to optimal T-cell activation, which is reflected in disease recovery, induction of neutralizing antibodies and long-term immunological memory. 3. A massive costimulation, inflammatory cytokine production and expression of epitopes restricted by non-protective HLA alleles, leads to T-cell hyperactivation, with increased production of inflammatory cytokines that can lead to severe disease/death, organ damage, chronic inflammation and possibly to post-VHF syndromes.

Figure 2

Kinetics of the cytokine response during VHF. Early during the acute phase of VHF, antigen-presenting cells produce high levels of type I IFN, and the inflammatory cytokines TNF-α and IL-6, that induce the activation of T-cells. This phase coincides with high levels of viremia that decreases after the fourth to fifth day after the onset of symptoms. The next period (from day 5 to 10) is characterized by the development of most disease complications, such as shock, hemorrhage and organ damage (shown as an orange region), coinciding with the massive activation of T-cells, and the increase in the levels of IFN-γ, IL-2, and IL-10. The period between days 4 to 12 is characterized by a massive cytokine production known as “cytokine storm” (shown as black line). Finally, the convalescence period coincides with the decrease in cytokine levels. In some VHF, the antigen persistence or perhaps epigenetic changes result in chronic T-cell activation, with increased levels of TNF-α and IFN-γ that are thought to be responsible for the development of post-VHF syndromes.

Figure 3

Dynamics of the human T-cell response after YF-17D vaccination. YF-17D replicates and exhibits a transient viremia, which stimulates the expansion of antigen-specific effector T-cells. This phase is followed by a contraction of the T-cell response, with massive death of effector populations. Finally, long-lived memory T-cells are observed after two to three months post-vaccination and remain detectable for at least 25 years. These memory populations are epigenetically poised to exert effector functions, and, after antigen re-stimulation, such as YF-17D boosters, a rapid differentiation of the effector profile is observed. However, the magnitude and quality of the remaining long-lived memory subsets are not influenced by vaccine boosters.

Figure 4

T-cell associated mechanisms of protection or susceptibility during VHF. T-cells can be activated in an antigen-specific or bystander manner, the latter through inflammatory cytokine signals. Bystander activation results in an exacerbated response of low-affinity cross-reactive T-cells (particularly during secondary infections of antigenically related viruses), that produce high levels of tumor necrosis factor (TNF)-α and other inflammatory cytokines and cytotoxic molecules, that associate with endothelial and/or hepatic damage. Antigen-specific priming of T-cells under the context of protective HLA alleles can lead to the generation of highly functional antigen-specific T-cells, which are characterized by the expression of inhibitory receptors such as programmed death (PD)-1, that can modulate their response and prevent hyperactivation. Individuals who maintain high frequencies of antigen-specific T-cells, despite increased apoptosis of these subsets, can preserve long-lasting immunity and protection against subsequent related viral infections.