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

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.

Hantavirus infection-induced B cell activation elevates free light chains levels in circulation

“…In addition, local production of FLCs in the kidneys could explain the lack of correlation between urinary FLC and serum FLC levels. The number of plasma cells in the kidneys positively correlated with the number of CD68+ and CD14+ cells ( S2B Fig ), which were previously analyzed from the same sample set [ 21 ] and likely represented macrophages and infiltrating monocytes, respectively. These results suggest a direct link between plasma cells and general inflammatory response in the kidneys during acute HFRS.…”

Innate lymphoid cells are activated and their levels correlate with viral load in patients with Puumala hantavirus caused hemorrhagic fever with renal syndrome

“…55–57 Mononuclear phagocytes are susceptible to infection with hantaviruses, and their activation and redistribution from circulation towards the airways and kidneys in HFRS patients have been reported. 58–61 Combined, these reports show that hantaviruses trigger strong immune cell responses, indicating a possible involvement of ILCs as well.…”

“…Whole blood samples were collected, and peripheral blood mononuclear cells (PBMCs) were isolated as previously described and stored in liquid nitrogen at -150°C, while plasma was stored at -80°C, until further use. 61…”

LncRNA NEAT1 Potentiates SREBP2 Activity to Promote Inflammatory Macrophage Activation and Limit Hantaan Virus Propagation

“…Mononuclear phagocytes (MNPs), which include monocytes and macrophages, were shown to facilitate hantaviral propagation and the immunopathogenesis of HFRS both in vivo and in vitro ( Scholz et al, 2017 ; Raftery et al, 2020 ; Vangeti et al, 2021 ). The replicative efficiency of hantaviruses in MNPs determines their pathogenicity in humans ( Raftery et al, 2020 ), and MNPs were also found to carry and spread PUUV from patient blood to the airway and kidneys during the acute phase of hantavirus disease ( Scholz et al, 2017 ; Vangeti et al, 2021 ). Exploring the endogenous anti-hantaviral factors in MNPs might reveal novel therapeutic avenues for HFRS.…”