Substance P receptor antagonist reverses intestinal pathophysiological alterations occurring in a novel ex-vivo model of Cryptosporidium parvum infection of intestinal tissues derived from SIV-infected macaques.
BACKGROUND
Cryptosporidium infection leads to life-threatening diarrhea in AIDS patients. Pathogenesis of cryptosporidiosis is due to intestinal physiological alterations. We devised an ex-vivo model using ex-vivo Cryptosporidium parvum infection of jejunal tissues derived from SIV-infected macaques and studied the role of substance P (SP) in the pathogenesis of cryptosporidiosis.


METHODS
We measured jejunal SP protein levels using ELISA, and electrophysiological alterations using the Ussing chamber technique in an ex vivo model of Cryptosporidium infection. Paraformaldehyde-fixed jejunum from SIV-infected macaques with and without naturally occurring cryptosporidiosis was studied for SP protein expression by immunohistochemistry and fluorescence deconvolution microscopy.


RESULTS
Ex-vivo Cryptosporidium-infected tissues and tissues from SIV-infected macaques with naturally occurring cryptosporidiosis demonstrated elevated SP protein levels compared with tissues from SIV-infected animals without ex-vivo C. parvum infection or tissues from SIV-infected animals that have no evidence of cryptosporidiosis. In our ex-vivo model of Cryptosporidium infection, we demonstrated pathophysiological alterations that were blocked by SP-receptor antagonist treatment.


CONCLUSIONS
These studies suggest that SP-receptor antagonists could prove useful for treatment of AIDS-related cryptosporidiosis.
Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX 77030, USA.
A
A
Garza
A
A
Lackner
P
P
Aye
M
M
D'Souza
P
P
Martin
J
J
Borda
D J
DJ
Tweardy
J
J
Weinstock
J
J
Griffiths
P
P
Robinson
D000818:Animals; D003457:Cryptosporidiosis; D016785:Cryptosporidium parvum / Q000502:physiology*; D005786:Gene Expression Regulation; D007583:Jejunum / Q000503:physiopathology*; D008251:Macaca; D064729:Neurokinin-1 Receptor Antagonists; D016097:Simian Acquired Immunodeficiency Syndrome / Q000150:complications*; D015302:Simian Immunodeficiency Virus; D013373:Substance P / Q000235:genetics / Q000378:metabolism; D046509:Tissue Culture Techniques
D064729:Neurokinin-1 Receptor Antagonists; D013373:Substance P