Rab GTPase regulation of bacteria and protozoa phagocytosis occurs through the modulation of phagocytic receptor surface expression

Elsa Seixas,Duarte C Barral,Cristina Escrevente,Miguel C Seabra

doi:10.1038/s41598-018-31171-5

Abstract

Phagocytosis of invading microorganisms by professional phagocytic cells has a central role in innate immunity. However, several microorganisms developed strategies to subvert this process. Previously, we reported that bacteria and protozoa modulate differently the expression of Rab GTPases. Moreover, our results suggested that this modulation can contribute to avoid phagocytosis. Here, we investigated the mechanism by which the malaria parasite Plasmodium berghei and the bacterium Escherichia coli subvert phagocytosis through the modulation of Rab14 or Rab9a expression, respectively. We first confirmed that the scavenger receptor CD36 and the Toll-like receptor (TLR) 4 are required for the phagocytosis of P. berghei and E. coli, respectively. Interestingly, we observed that Rab14 silencing leads to an increase in the surface expression of CD36 in macrophages, which can explain the increase in the phagocytosis of P. berghei we reported previously. Similar results were obtained for Rab9a and TLR4, i.e. Rab9a silencing causes an upregulation of TLR4 surface expression in macrophages. Furthermore, we found that the decrease in the internalization of CD36 and TLR4, upon Rab14 or Rab9a silencing, respectively, can explain the increase in the surface levels of these receptors. Thus, our studies provide evidence that the modulation of phagocytosis caused by changes in Rab expression is operated, at least partly through changes in the surface levels of phagocytic receptors.

Highlights

The innate immune system is the first line of defense against invading microorganisms
We confirmed that TLR4 is a receptor involved in the phagocytosis of E. coli and its surface levels increase in macrophages silenced for Rab9a, which can explain the increase in phagocytosis we have reported
To determine if CD36 and TLR4 are involved in the increase in phagocytosis observed, we investigated the role of these receptors in the phagocytosis of P. berghei and E. coli, respectively

Summary

Introduction

The innate immune system is the first line of defense against invading microorganisms. Professional phagocytic cells such as macrophages, dendritic cells and monocytes play a crucial role in the innate immune response and host defense Central to this response is the expression of pattern recognition receptors (PRRs), such as scavenger receptors, which bind a broad array of modified and foreign ligands[1]. Similar results were obtained with E. coli and Rab9a, i.e. infection with E. coli increases the expression of Rab9a and Rab9a overexpression impairs the phagocytosis of E. coli, whereas Rab9a silencing has the opposite effect These results suggest that P. berghei and E. coli modulate the expression of Rab proteins to their own advantage. We confirmed that TLR4 is a receptor involved in the phagocytosis of E. coli and its surface levels increase in macrophages silenced for Rab9a, which can explain the increase in phagocytosis we have reported. Our studies suggest that the changes in phagocytosis caused by the modulation of Rab[14] and Rab9a expression are caused, at least in part by changes in the surface levels of CD36 and TLR4, respectively

Methods

Results

Conclusion