Simultaneous analysis of host and pathogen interactions during an in vivo infection reveals local induction of host acute phase response proteins, a novel bacterial stress response, and evidence of a host-imposed metal ion limited environment.
A fundamental goal in the study of infections is to understand the dynamic interplay between host and pathogen; however, direct in vivo interrogation of this disease process via transcriptional profiling has been lacking. Here we describe the development and application of novel bacterial RNA amplification technology to simultaneously identify key elements of both host and pathogen responses in a murine infection model. On the bacterial side, we found induction of an unusual pattern of stress response genes, a response to host-induced metal ion limitation, and a failure to achieve stationary phase in vivo. On the mammalian side, we observed the surprising induction of several genes encoding acute phase response proteins including hepcidin, haptoglobin, complement C3 and metallothionein 1 at the site of infection, as well as other mediators of innate immunity. Thus, our results reveal host-pathogen cross-talk not predicted by previous in vitro analyses and provide the framework to eavesdrop on a broad array of host-pathogen interactions in vivo. As described here, the comprehensive examination of host-pathogen interactions during an infection is critical to the discovery of novel approaches for intervention not predicted by current models.
Motley
S Timothy
ST
Johnson & Johnson Pharmaceutical Research and Development, L. L. C. 3210 Merryfield Row, La Jolla, CA 92121, USA.
Morrow
Brian J
BJ
Liu
Xuejun
X
Dodge
Ingrid L
IL
Vitiello
Antonella
A
Ward
Christine K
CK
Shaw
Karen Joy
KJ
D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D004927:Escherichia coli Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015964:Gene Expression Regulation, Bacterial; D005796:Genes; D005798:Genes, Bacterial; D006099:Granuloma / Q000378:metabolism / Q000382:microbiology; D006242:Haptoglobins / Q000235:genetics / Q000378:metabolism; D064451:Hepcidins; D006801:Humans; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism; D008670:Metals / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D012329:RNA, Bacterial / Q000378:metabolism; D018085:Regulon
D000209:Acute-Phase Proteins; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D003176:Complement C3; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D006242:Haptoglobins; D064451:Hepcidins; D008670:Metals; D012329:RNA, Bacterial; D008668:Metallothionein