Chlamydial IFN-gamma immune evasion is linked to host infection tropism.
Chlamydiae are obligate intracellular pathogens that can exhibit a broad host range in infection tropism despite maintaining near genomic identity. Here, we have investigated the molecular basis for this unique host-pathogen relationship. We show that human and murine chlamydial infection tropism is linked to unique host and pathogen genes that have coevolved in response to host immunity. This intimate host-pathogen niche revolves around a restricted repertoire of host species-specific IFN-gamma-mediated effector responses and chlamydial virulence factors capable of inhibiting these effector mechanisms. In human epithelial cells, IFN-gamma induces indoleamine 2,3-dioxygenase expression that inhibits chlamydial growth by depleting host tryptophan pools. Human chlamydial strains, but not the mouse strain, avoid this response by the production of tryptophan synthase that rescues them from tryptophan starvation. Conversely, in murine epithelial cells IFN-gamma induces expression of p47 GTPases, but not indoleamine 2,3-dioxygenase. One of these p47 GTPases (Iigp1) was shown by small interfering RNA silencing experiments to specifically inhibit human strains, but not the mouse strain. Like human strains and their host cells, the murine strain has coevolved with its murine host by producing a large toxin possessing YopT homology, possibly to circumvent host GTPases. Collectively, our findings show chlamydial host infection tropism is determined by IFN-gamma-mediated immunity.
Nelson
David E
DE
Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, National Institutes of Health, Hamilton, MT 59840, USA.
Virok
Dezso P
DP
Wood
Heidi
H
Roshick
Christine
C
Johnson
Raymond M
RM
Whitmire
William M
WM
Crane
Deborah D
DD
Steele-Mortimer
Olivia
O
Kari
Laszlo
L
McClarty
Grant
G
Caldwell
Harlan D
HD
D000818:Animals; D002690:Chlamydia Infections / Q000235:genetics / Q000276:immunology*; D002692:Chlamydia trachomatis / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D004847:Epithelial Cells / Q000276:immunology; D019143:Evolution, Molecular; D005260:Female; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology*; D051379:Mice; D046228:Microarray Analysis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010057:Oviducts / Q000166:cytology* / Q000276:immunology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014364:Tryptophan / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D037521:Virulence Factors; D007371:Interferon-gamma; D014364:Tryptophan; D052247:Nitric Oxide Synthase Type II; D020558:GTP Phosphohydrolases