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Review
. 2019 May;285(5):510-523.
doi: 10.1111/joim.12876. Epub 2019 Feb 17.

Innate and Adaptive Immune Responses Against Human Puumala Virus Infection: Immunopathogenesis and Suggestions for Novel Treatment Strategies for Severe Hantavirus-Associated Syndromes

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Free PMC article
Review

Innate and Adaptive Immune Responses Against Human Puumala Virus Infection: Immunopathogenesis and Suggestions for Novel Treatment Strategies for Severe Hantavirus-Associated Syndromes

J Klingström et al. J Intern Med. .
Free PMC article

Abstract

Two related hyperinflammatory syndromes are distinguished following infection of humans with hantaviruses: haemorrhagic fever with renal syndrome (HFRS) seen in Eurasia and hantavirus pulmonary syndrome (HPS) seen in the Americas. Fatality rates are high, up to 10% for HFRS and around 35%-40% for HPS. Puumala virus (PUUV) is the most common HFRS-causing hantavirus in Europe. Here, we describe recent insights into the generation of innate and adaptive cell-mediated immune responses following clinical infection with PUUV. First described are studies demonstrating a marked redistribution of peripheral blood mononuclear phagocytes (MNP) to the airways, a process that may underlie local immune activation at the site of primary infection. We then describe observations of an excessive natural killer (NK) cell activation and the persistence of highly elevated numbers of NK cells in peripheral blood following PUUV infection. A similar vigorous CD8 Tcell response is also described, though Tcell responses decline with viraemia. Like MNPs, many NK cells and CD8 T cells also localize to the lung upon acute PUUV infection. Following this, findings demonstrating the ability of hantaviruses, including PUUV, to cause apoptosis resistance in infected target cells, are described. These observations, and associated inflammatory cytokine responses, may provide new insights into HFRS and HPS disease pathogenesis. Based on similarities between inflammatory responses in severe hantavirus infections and other hyperinflammatory disease syndromes, we speculate whether some therapeutic interventions that have been successful in the latter conditions may also be applicable in severe hantavirus infections.

Keywords: Puumala virus; haemorrhagic fever with renal syndrome; hantavirus; hantavirus pulmonary syndrome; orthohantavirus; viral immunity.

Conflict of interest statement

No one of the authors have any conflict of interest in relation to the work reviewed in this paper.

Figures

Figure 1
Figure 1
Transmission of pathogenic hantaviruses including Puumala virus (PUUV) to humans occurs predominantly through the inhalation of dust containing virus‐contaminated rodent excreta (illustrated in the upper part of the Figure). In a global perspective, two main hyperinflammatory clinical syndromes can be distinguished following infection with different species of hantaviruses: haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). HFRS is the predominant hantavirus‐induced disease syndrome in Eurasia whilst HPS dominates in the Americas. Many aspects of HFRS and HPS are shared between the two diseases, and the pathogenesis is likely similar even if there are some differences in organ manifestations and, importantly, in severity (illustrated in the lower part of the Figure). In the present review, we discuss recent insights into the innate and adaptive cell‐mediated immune responses to human PUUV infection.
Figure 2
Figure 2
Infiltration of antigen‐presenting cells and other immune cells in the airways during acute Puumala virus‐caused HFRS. Shown are representative images of HLA‐DR staining in endobronchial biopsies in acute HFRS. Specific staining appears in red, and cell nuclei are counterstained with haematoxylin in blue 17. Visualization was performed using immunohistochemistry. Scale bar, 50 μm.
Figure 3
Figure 3
NK cell and T‐cell immune responses observed following Puumala virus (PUUV) infection. Generally, in viral infections, innate immune responses peak after a few days. In contrast, in a cohort of hospitalized PUUV‐infected individuals, a strong NK cell response was elicited and cell numbers remained elevated over several weeks well beyond the resolution of viraemia. The patients also displayed a vigorous, albeit transient, CD8 T‐cell response largely coinciding with viraemia.
Figure 4
Figure 4
Similarities between inflammatory responses in severe hantavirus infections and other, nonrelated, hyperinflammatory disease syndromes. Cytotoxic cells of the immune system, such as natural killer (NK) cells and cytotoxic T cells (CTL), normally possess the capacity to kill virus‐infected cells and tumour cells (panel 1). Killing does however not always occur. In rare cases, such as in familial lymphohistiocytosis (FHL), mutations in genes affecting production of proteins such as perforin or proteins affecting degranulation lead to an impaired elimination of target cells (panel 2). In other cases, such as cancer, CTL cells may encounter apoptosis‐resistant tumour cells (panel 3). Finally, in the case of hantavirus infection, including Puumala virus infection, cytotoxic cells likewise encounter apoptosis‐resistant cells (panel 4). Interestingly, all displayed conditions above (illustrated in panels 2–4) are associated with severe inflammation or ‘cytokine release syndromes’ (CRS). Handling of these often‐severe clinical conditions differs. In the case of reducing CRS in FHL (panel 2), immunochemotherapy (dexamethasone and etoposide) has been successfully implemented as a treatment strategy. In the case of reducing CRS following adoptive CAR‐T cell treatment (panel 3), treatment interfering with IL‐6 signalling has proven efficient. The question is whether any of the latter two treatment strategies could find a role in severe clinical hantavirus infection (panel 4).

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