Septic shock and nonpulmonary organ dysfunction in pneumonic plague: the role of Yersinia pestis pCD1- vs. pgm- virulence factors.
OBJECTIVE
Pneumonic plague resulting from Yersinia pestis induces swiftly lethal sepsis and is a major concern as a weapon of bioterrorism. However, the role of specific plasmid-encoded vs. chromosomal Y. pestis virulence factors in the pathogenesis of acute lung injury, shock, and nonpulmonary dysfunction is unclear. We hypothesized that the pathophysiology of pneumonic plague resulting from expression of proteins encoded by the thermally regulated pCD1 plasmid differs from cardiopulmonary and inflammatory changes attributable to the chromosomal pgm gene locus.


METHODS
Prospective, experimental study.


METHODS
Research laboratory at a university medical center.


METHODS
Conscious, chronically catheterized male Sprague-Dawley rats (total n=104).


METHODS
Rats were intratracheally infected with 109 colony-forming units of Y. pestis attenuated strains CO99 (pCD1+/DeltaApgm) or KIM6+ (pCD1-/pgm+) and evaluated over 6 days. Serial evaluations of vital signs, cardiorespiratory parameters, blood cultures, inflammatory biomarkers, and organ function were obtained, as well as organ histopathology and cytokine production.


RESULTS
Despite equivalent endotoxin contents between the inocula, CO99-infected animals had a median survival of 3 days with greater nonpulmonary organ injury, microbial growth, serum alanine aminotransferase, and liver microvascular permeability vs. KIM6+-infected animals (p<.05). Parallel differences occurred in serum tumor necrosis factor-alpha levels. Notably, 75% of CO99 rats developed fatal hypotension after developing nonpulmonary organ damage.


CONCLUSIONS
These results suggest that progression to lethal sepsis with augmented liver injury during plague pneumonia requires factors encoded by the pCD1 plasmid but not chromosomal proteins present within the pgm gene locus.
Doyle
Timothy M
TM
Department of Pharmacological & Physiological Science, St Louis University School of Medicine, St Louis, MO, USA.
Matuschak
George M
GM
Lechner
Andrew J
AJ
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000502:physiology*; D002199:Capillary Permeability; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005798:Genes, Bacterial; D056426:Genetic Loci; D006439:Hemodynamics; D008099:Liver / Q000098:blood supply; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology / Q000382:microbiology / Q000503:physiopathology*; D010930:Plague / Q000150:complications / Q000382:microbiology / Q000503:physiopathology*; D010957:Plasmids; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000209:etiology / Q000382:microbiology / Q000503:physiopathology*; D037521:Virulence Factors / Q000235:genetics / Q000502:physiology*; D015010:Yersinia pestis / Q000235:genetics / Q000502:physiology*
D001426:Bacterial Proteins; D016207:Cytokines; D037521:Virulence Factors; D000410:Alanine Transaminase