Lessons from reservoirs

    Recent evidence shows that both acute and chronic infections can persist in tissue reservoirs that act as a source of subsequent disease. Identifying the parallels of reservoir maintenance by diverse pathogens might offer new leads to enable their control.

    HIV does it. Zika virus does it. Herpesviruses, Ebola virus, bacteria, protozoan parasites, and helminths do it. These pathogens can all hide in dormant, or latent, forms in their human host, to re-emerge later, often under conditions of cellular stress. We rarely discuss the similarities that they share in this trait. But there is merit in exploring the mechanisms that maintain the in vivo reservoir of one latent pathogen to advance our understanding of another.

    Although reservoirs are integral to pathogen persistence, they are frequently understudied, at least in the context of acutely infecting microbes. One reason for this is that in the absence of symptoms or evidence of measurable replication from primary sites of infection, the infectious agent is thought to be eliminated. However, recent research suggests that our knowledge of pathogen dynamics during acute infection is incomplete. Likewise, we lack a comprehensive appreciation of the range of cells and tissues infiltrated by chronic infections and of the interaction of these cellular reservoirs with the host immune system.

    Consider the example of Ebola virus (EBOV). At least two individuals thought to have been cured of EBOV infection following experimental treatments developed symptoms of ocular and central nervous system (CNS) inflammation about a year afterward, in the absence of measurable virus in the blood. Detection of the virus in the eye and brain, respectively, revealed that EBOV can persist hidden in immune-privileged sites. Additionally, two cases of sexual transmission of EBOV indicated that the virus can exist for months in an infection-competent form in the seminal fluid of some survivors. And a recent study of tissues from 112 rhesus monkeys that survived experimental exposure to EBOV found viral RNA in the eye, brain, and testes of 11 animals, and suggested that macrophages might act as reservoir cells for the virus (Nat. Microbiol. 2, 17113, 2017).

    What do these findings tell us? That the immune system can control EBOV infection—up to a point. But we don't know how long the attendant inflammation can hold the virus in check, or why, in the cases described above, the virus failed to overcome those immune defenses to cause rebound of systemic viremia. We do know that the clinical and preclinical evidence of viral persistence highlights the need for further research and monitoring of EBOV survivors for treatment of flare-ups and to prevent subsequent outbreaks, as well as to determine which host and virus parameters enable temporarily asymptomatic sequestration of the pathogen.

    Similar to EBOV, Zika virus (ZIKV) was initially thought to cause an acute infection—albeit nonlethal in most adults—that concluded with elimination of the virus from the body. But the recent outbreak in South America that led to the identification of ZIKV as the cause of microcephaly and other birth defects (known as congenital Zika syndrome) in infants of mothers infected during pregnancy stimulated a surge in research on the virus. This flurry of investigation revealed that, in fact, ZIKV can persist asymptomatically in the urine and semen of individuals, and several instances of sexual transmission of ZIKV have now been reported.

    Moreover, in a study of rhesus macaques infected with ZIKV, researchers detected the prolonged presence of viral RNA in cerebrospinal fluid (CSF), lymph nodes and colorectal tissue after the virus had cleared from blood and plasma (Cell 169, 610–620, 2017). In these animals, the expression of proinflammatory-, mTOR- and anti-apoptosis pathway–associated genes in the blood or lymph nodes correlated with persistent viral loads (in the CSF or lymph nodes, respectively), which may suggest that the survival of infected cells, coupled with the activation of innate immune responses, facilitated a controlled and transient viral persistence. In contrast to blood, CSF of infected animals lacked virus-specific antibodies, which may have contributed to virus sequestration in that compartment. The direct mechanisms underlying virus persistence, and the extent to which it can cause delayed disease sequelae in the primary infected host or acute infection after transmission to a second animal, remain to be elucidated. But encouraging more of these types of studies can help to uncover patterns of viral spread within and among populations that are important to developing effective control measures.

    Even in the case of HIV, which, unlike EBOV and ZIKV, has a long history of reservoir research and escapes elimination by integrating into the host genomic DNA, the picture is not complete. Whereas resting memory CD4+ T cells are considered to be the primary latent cell reservoir of HIV, myeloid cells can sustain infection in humanized mice, and infected macrophages have been detected in the CNS of individuals positive for HIV infection. Other cell types could theoretically have a direct or indirect role in maintaining the viral reservoir or in mediating its reactivation. And cellular reservoirs are only part of the story—tissue architecture and cellular cross-talk play a part, as suggested by reports of sequestration and low-level replication of HIV in lymph nodes. Notably, in instances of delayed rebound of detectable HIV in individuals after the cessation of antiretroviral therapy, the rebounding virus may derive from multiple cellular and tissue sources.

    Although pathogens may employ different tricks to mediate latency and to avoid detection or eradication, the host pathways that they are designed to evade—such as pathogen-associated molecular pattern signaling, antigen processing and immune recognition, or cell death—may be common to acute and chronic infections. Identifying the conditions and cellular triggers that contribute to latency induction and to pathogen reactivation will serve research on pathogens of all types.

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    Lessons from reservoirs. Nat Med 23, 899 (2017). https://doi.org/10.1038/nm.4387

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