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Adaptive immune responses to primary and secondary dengue virus infections

Abstract

Dengue is the leading mosquito-borne viral illness infecting humans. Owing to the circulation of multiple serotypes, global expansion of the disease and recent gains in vaccination coverage, pre-existing immunity to dengue virus is abundant in the human population, and secondary dengue infections are common. Here, we contrast the mechanisms initiating and sustaining adaptive immune responses during primary infection with the immune pathways that are pre-existing and reactivated during secondary dengue. We also discuss new developments in our understanding of the contributions of CD4+ T cells, CD8+ T cells and antibodies to immunity and memory recall. Memory recall may lead to protective or pathological outcomes, and understanding of these processes will be key to developing or refining dengue vaccines to be safe and effective.

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Acknowledgements

The authors acknowledge funding from the National Medical Research Council of Singapore (NMRC/CBRG/0084/2015), the National Research Foundation of Singapore (NRF2016NRF-CRP001-063) and Duke–National University of Singapore (NUS) Medical School to A.L.S.

Reviewer information

Nature Reviews Immunology thanks S. Halstead, A. Sette, and other anonymous reviewer(s) for their contribution to the peer review of this work.

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The authors contributed equally to all aspects of the article.

Correspondence to Ashley L. St. John.

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Glossary

DENV serotypes

All four serotypes of dengue virus (DENV) share similar but distinct antigenic properties. Polyclonal sera raised to one DENV serotype can bind to all four DENV serotypes and may be minimally neutralizing but will efficiently neutralize and provide long-term protection against only the same serotype. DENV serotypes have ~50–60% sequence homology.

Type I interferon

A group of proteins, including IFNα and IFNβ, that are produced and secreted by cells activated by certain stimuli, including infection, for the purpose of host defence. Often, these interferon proteins have antiviral function.

Heterologous DENV infection

A dengue infection with one dengue virus (DENV) serotype following a primary infection by a different DENV serotype. For instance, DENV1 infection followed by DENV2 infection.

Homologous DENV infection

This refers to a secondary dengue virus (DENV) infection with the same serotype that caused the primary infection. For example, DENV1 infection followed by a secondary DENV1 infection.

T effector memory RA cells

(TEMRA cells). Terminally differentiated antigen-specific memory T cells that re-express CD45RA. These cells have been identified in both CD4+ and CD8+ T cell compartments and can have a cytotoxic phenotype.

Original antigenic sin

Reactivation and expansion of an immune memory response that was formed in response to a previous infection upon exposure to a second infection from a pathogen that has similar but distinct antigenic properties to that of the first pathogen. This results in a skewed and potentially suboptimal immune response generated during infection by the second pathogen.

Serocomplexes

Groups of antigenically related viruses cluster into serocomplexes on the basis of serological assessments. Polyclonal sera against one virus may bind to but will not neutralize viruses of another serocomplex. Important mosquito-borne human flaviviral pathogens that are clustered in different serocomplexes include dengue virus serotype 1 (DENV1) and DENV4 (DENV serocomplex), Japanese encephalitis virus (JEV) and West Nile virus (JEV serocomplex), and Spondweni virus and Zika virus (Spondweni serocomplex).

Reverse Arthus reaction

The immune complex-mediated vasculitis in a type III hypersensitivity reaction that results from the injection of antibodies into the skin following passive infusion of antigen.

Antibody-dependent cellular cytotoxicity

An immune phenomenon where crystallizable fragment (Fc) receptor-bearing cytotoxic immune cells can recognize and lyse antibody-coated, antigen-expressing cells. Antigens that can lead to antibody-dependent cellular cytotoxicity may arise owing to infection.

Antigenic seniority

First described in the context of antibody responses to influenza, this refers to the observation that during repeated infections with related viruses, immune responses are skewed towards the original strain encountered. Similar to original antigenic sin, this concept incorporates the idea that antigenic exposure to similar viruses is influenced by the genetic relationships between them and that certain epitopes of ‘senior strains’ experienced early in life will begin to dominate the immune responses during subsequent exposures to related pathogens.

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Further reading

Fig. 1: Time course of acute infection and immune responses during symptomatic dengue virus infection.
Fig. 2: Initiation of anti-dengue virus immunity in the skin and draining lymph nodes.
Fig. 3: Adaptive T cell responses during dengue virus infection.
Fig. 4: Antibody-dependent pathologies during dengue virus infections.
Fig. 5: Theories of T cell contributions to dengue virus protection versus pathology.