Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

HIF-alpha Activation Impacts Macrophage Function During Murine Leishmania major Infection

Version 1 : Received: 5 October 2021 / Approved: 7 October 2021 / Online: 7 October 2021 (11:00:12 CEST)

A peer-reviewed article of this Preprint also exists.

Bettadapura, M.; Roys, H.; Bowlin, A.; Venugopal, G.; Washam, C.L.; Fry, L.; Murdock, S.; Wanjala, H.; Byrum, S.D.; Weinkopff, T. HIF-α Activation Impacts Macrophage Function during Murine Leishmania major Infection. Pathogens 2021, 10, 1584. Bettadapura, M.; Roys, H.; Bowlin, A.; Venugopal, G.; Washam, C.L.; Fry, L.; Murdock, S.; Wanjala, H.; Byrum, S.D.; Weinkopff, T. HIF-α Activation Impacts Macrophage Function during Murine Leishmania major Infection. Pathogens 2021, 10, 1584.

Journal reference: Pathogens 2021, 10, 1584
DOI: 10.3390/pathogens10121584

Abstract

Leishmanial skin lesions are characterized by inflammatory hypoxia alongside the activation of hypoxia inducible factors, HIF-1a and HIF-2a, and subsequent expression of the HIF-a target VEGF-A during Leishmania major infection. However, the factors responsible for HIF-a activation are not known. We hypothesize hypoxia and pro-inflammatory stimuli contribute to HIF-a activation during infection. RNASeq on leishmanial lesions found transcripts associated with HIF-1a signaling are induced. To determine whether hypoxia contributes to HIF-a activation, we followed the fate of myeloid cells infiltrating from the blood and into hypoxic lesions. Recruited myeloid cells experience hypoxia when they enter inflamed lesions, and the length of time in lesions increases their hypoxic signature. To determine whether pro-inflammatory stimuli in the inflamed tissue can also influence HIF-a activation, we subjected macrophages to various pro-inflammatory stimuli and measured VEGF-A. While parasites alone did not induce VEGF-A, and pro-inflammatory stimuli only modestly induce VEGF-A, HIF- stabilization increases VEGF-A during infection. HIF-a stabilization does not impact parasite entry, growth or killing. Alternatively, the absence of ARNT/HIF- signaling enhances parasite internalization. Altogether, these findings suggest HIF-a is active during infection, and while macrophage HIF-a activation promotes lymphatic remodeling through VEGF-A production, HIF-a activation does not impact parasite internalization or control.

Keywords

Leishmania; leishmaniasis; macrophages; HIF-alpha

Subject

LIFE SCIENCES, Microbiology

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