Monocyte subset redistribution from blood to kidneys in patients with Puumala virus caused hemorrhagic fever with renal syndrome.

Sindhu Vangeti,Antti Vaheri,Satu Mäkelä,Antti Hassinen,Sang Liu,Luz Cabrera,Jukka Mustonen,Johanna Tauriainen,Anne Räisänen-Sokolowski,Tomas Strandin,Anna Smed-Sörensen,Olli Vapalahti,Jonas Klingström

doi:10.1371/journal.ppat.1009400

Abstract

Innate immune cells like monocytes patrol the vasculature and mucosal surfaces, recognize pathogens, rapidly redistribute to affected tissues and cause inflammation by secretion of cytokines. We previously showed that monocytes are reduced in blood but accumulate in the airways of patients with Puumala virus (PUUV) caused hemorrhagic fever with renal syndrome (HFRS). However, the dynamics of monocyte infiltration to the kidneys during HFRS, and its impact on disease severity are currently unknown. Here, we examined longitudinal peripheral blood samples and renal biopsies from HFRS patients and performed in vitro experiments to investigate the fate of monocytes during HFRS. During the early stages of HFRS, circulating CD14-CD16+ nonclassical monocytes (NCMs) that patrol the vasculature were reduced in most patients. Instead, CD14+CD16- classical (CMs) and CD14+CD16+ intermediate monocytes (IMs) were increased in blood, in particular in HFRS patients with more severe disease. Blood monocytes from patients with acute HFRS expressed higher levels of HLA-DR, the endothelial adhesion marker CD62L and the chemokine receptors CCR7 and CCR2, as compared to convalescence, suggesting monocyte activation and migration to peripheral tissues during acute HFRS. Supporting this hypothesis, increased numbers of HLA-DR+, CD14+, CD16+ and CD68+ cells were observed in the renal tissues of acute HFRS patients compared to controls. In vitro, blood CD16+ monocytes upregulated CD62L after direct exposure to PUUV whereas CD16- monocytes upregulated CCR7 after contact with PUUV-infected endothelial cells, suggesting differential mechanisms of activation and response between monocyte subsets. Together, our findings suggest that NCMs are reduced in blood, potentially via CD62L-mediated attachment to endothelial cells and monocytes are recruited to the kidneys during HFRS. Monocyte mobilization, activation and functional impairment together may influence the severity of disease in acute PUUV-HFRS.

Highlights

Hantaviruses are zoonotic viruses that pose a clear burden to human health [1,2]
The vascular leakage associated with hantavirus disease, and hemorrhagic fever with renal syndrome (HFRS) is believed to be a consequence of the dysregulated immune response to infection
In a cohort of PUUVinfected patients with acute HFRS, we describe a striking depletion of nonclassical monocytes from circulation while classical and intermediate monocyte frequencies are increased

Summary

Introduction

Hantaviruses (genus Orthohantavirus, family Hantaviridae, Order Bunyavirales) are zoonotic viruses that pose a clear burden to human health [1,2]. “old world”) cause hemorrhagic fever with renal syndrome (HFRS) whereas hantaviruses of the Americas “new world”) can cause hantavirus pulmonary syndrome (HPS) [1,4,5,6]. The most affected organ varies from kidneys in HFRS to lungs in HPS, a hallmark of both diseases is increased vascular leakage. Microvascular endothelial cells, that form the barrier between the capillary bloodstream and tissues, are the prime target cells of hantavirus infection in humans but the virus itself does not directly affect endothelial cell permeability. Vascular leakage is likely a consequence of an excessive immune response to hantavirus infections [6,7,8], and several immune-related processes have been suggested to be involved [9,10,11]

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