The two faces of heterologous immunity: protection or immunopathology

Abstract

Immunity to previously encountered viruses can alter responses to unrelated pathogens. This phenomenon, which is known as heterologous immunity, has been well established in animal model systems. Heterologous immunity appears to be relatively common and may be beneficial by boosting protective responses. However, heterologous reactivity can also result in severe immunopathology. The key features that define heterologous immune modulation include alterations in the CD4(+) and CD8(+) T cell compartments and changes in viral dynamics and disease progression. In this review, we discuss recent advances and the current understanding of antiviral immunity in heterologous infections. The difficulties of studying these complex heterologous infections in humans are discussed, with special reference to the variations in HLA haplotypes and uncertainties about individuals' infection history. Despite these limitations, epidemiological analyses in humans and the data from mouse models of coinfection can be applied toward advancing the design of therapeutics and vaccination strategies.

Keywords: T cell repertoire; attrition; bystander activation; cross-reactivity; heterologous viral infections; immunity; immunodominance.

Figure 1.. Outcome of infection following heterologous viral infections is dependent on the features of the immune response to a simultaneously or previously encountered pathogen.

As an example, for simultaneous or staggered infections with two distinct viruses: (A) dimultaneous infection can enhance immunopathology, potentially as a result of the immune responses to both viruses, reaching peak levels at the same time. (B) Prior infection can result in activation of APC so that a subsequent infection encounters mature APC, resulting in more efficient antigen presentation and faster disease progression and resolution. Also, the new, incoming pathogen creates a strong antiviral state that might result in reduced viral loads of first pathogen. (C) Upon activation, APCs secrete cytokines that result in Th subset differentiation so that a heterologous, incoming pathogen encounters an already polarized immune response. Encounter with a Th1 type of immune response can provide bystander protection against some pathogens or enhanced immunopathology, whereas Tregs can result in suppression of immune responses to incoming pathogen, which may be protective or pathogenic. (D) Subsequent heterologous infection in the presence of an ongoing effector CD8⁺ T cell response can result in bystander protection from IFN-γ production. (E) When a new virus infects the host with an established memory CD8⁺ T cell pool, the outcome may be cross-reactivity (can be protective or pathogenic), which can lead to recruitment of a cross-reactive T cell pool, resulting in a narrowed repertoire and altered immunodominance hierarchies. (F) Reciprocally, the incoming pathogen can result in bystander activation or attrition (Type 1 IFN-dependent) of pre-existing memory CD8 T cells. The specific outcome of heterologous viral infection depends on the type and sequence of viruses.