Alpha-1 antitrypsin is markedly decreased following pulmonary F. tularensis challenge.
Neutrophils form the first line of defense during infection and are indispensable in this function. The neutrophil elastase is a key effector molecule of the innate immune system with potent antimicrobial activity against Gram-negative bacteria, spirochaetes, and fungi. However, the release of neutrophil elastase during bacterial infection must be checked otherwise its release in the extracellular milieu will result in damage to surrounding tissues. Alpha-1 antitrypsin is a small glycoprotein clade A serpine serine protease inhibitor and has been shown to increase in humans following bacterial and viral infection. Francisella tularensis is a Gram-negative facultative intracellular bacterium and the causative agent of tularemia. Type A strains are the most virulent with an infectious dose as low as 10 colony forming units and a mortality rate of 30-60% among untreated cases of pneumonic tularemia. We report here significant reduction of this major inhibitor of the neutrophil elastase in plasma of F. tularensis LVS and F. tularensis (type A) SCHU S4 infected animals following pulmonary challenge. Associated with an imbalance of protease-antiprotease function at the alveolar level in lungs of infected animals, increased elastase activity was observed in lung lavage fluids accompanied by decrease lung function, i.e., loss of lung elastance with concomitant increase of pulmonary hysteresivity. Consistent with a competent acute phase response following F. tularensis LVS and F. tularensis (type A) SCHU S4 pulmonary challenge and proposed up-regulation of plasma haptoglobin during the course of the acute phase reaction, haptoglobin was observed significantly increased. These data suggest that unchecked neutrophil serine protease activity may arise from F. tularensis targeted reduction of plasma α(1)-antitrysin promoting lung tissue damage facilitating increased dissemination of this bacterium in infected animals.
Department of Biology, South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio, San Antonio, TX, USA; Department of Biology, Center of Excellence in Infection Genomnics, The University of Texas at San Antonio, San Antonio, TX, USA. james.chambers@utsa.edu
James P
JP
Chambers
Jieh-Juen
JJ
Yu
Madhulika
M
Jupelli
Susan T
ST
Weintraub
Jose L
JL
Lopez-Ribot
James J
JJ
Valdes
Bernard P
BP
Arulanandam
D000818:Animals; D005260:Female; D005604:Francisella tularensis / Q000145:classification / Q000276:immunology / Q000472:pathogenicity*; D006242:Haptoglobins / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D019272:Leukocyte Elastase / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology / Q000382:microbiology; D053491:Proteinase Inhibitory Proteins, Secretory / Q000097:blood; D014406:Tularemia / Q000209:etiology* / Q000276:immunology* / Q000503:physiopathology; D014774:Virulence / Q000276:immunology; D000515:alpha 1-Antitrypsin / Q000097:blood*
D006242:Haptoglobins; D053491:Proteinase Inhibitory Proteins, Secretory; D000515:alpha 1-Antitrypsin; D019272:Leukocyte Elastase