Complement C3 as a Prompt for Human Macrophage Death during Infection with Francisella tularensis Strain SCHU S4.

Abstract:

:Tularemia is caused by the Gram-negative bacterial pathogen Francisella tularensis Infection of macrophages and their subsequent death are believed to play important roles in the progression of disease. Because complement is a particularly effective opsonin for Francisella, we asked whether complement-dependent uptake of F. tularensis strain SCHU S4 affects the survival of primary human macrophages during infection. Complement component C3 was found to be an essential opsonin in human serum not only for greatly increased uptake of SCHU S4 but also for the induction of macrophage death. Single-cell analysis also revealed that macrophage death did not require a high intracellular bacterial burden. In the presence of C3, macrophage death was observed at 24 h postinfection in a quarter of the macrophages that contained only 1 to 5 bacterial cells. Macrophages infected in the absence of C3 rarely underwent cell death, even when they contained large numbers of bacteria. The need for C3, but not extensive replication of the pathogen, was confirmed by infections with SCHU S4 ΔpurMCD, a mutant capable of phagosome escape but of only limited cytosolic replication. C3-dependent Francisella uptake alone was insufficient to induce macrophage death, as evidenced by the failure of the phagosome escape-deficient mutant SCHU S4 ΔfevR to induce cell death despite opsonization with C3. Together, these findings indicate that recognition of C3-opsonized F. tularensis, but not extensive cytosolic replication, plays an important role in regulating macrophage viability during intracellular infections with type A F. tularensis.

journal_name

Infect Immun

journal_title

Infection and immunity

authors

Brock SR,Parmely MJ

doi

10.1128/IAI.00424-17

subject

Has Abstract

pub_date

2017-09-20 00:00:00

issue

10

eissn

0019-9567

issn

1098-5522

pii

IAI.00424-17

journal_volume

85

pub_type

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