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ABSTRACTS – Symposia
in the presence of numerous inhibitors that target host cell
signaling proteins. We then measured the number of host
cell-internalized bacteria and levels of IL-8 secreted into the
supernatants.
We found that many of the host cell proteins required for
C. jejuni internalization and the IL-8 inflammatory response
are the same (i.e., EGFR, FAK, Src, PI 3-kinase). We also
identified a C. jejuni secreted protein, which we termed CiaD,
that activates the mitogen-activated protein kinase (Erk 1/2)
pathway necessary for the secretion of IL-8 from epithelial
cells. These findings are consistent with the proposal that the
C. jejuni Cia proteins promote intracellular signaling leading
to bacterial uptake and the release of the pro-inflammatory
cytokine IL-8.
85 Effects of Selective and Non-selective NSAIDs on Initiation,
Progression and Antibiotic Efficacy of Experimental
Group A Streptococcal Myonecrosis, Stephanie Ham-
ILTON 1,2 *, Clifford R Bayer 1 , Dennis L Stevens
1,3 , and Amy E Bryant 1,2,3 ( 1 U.S. Department
of Veterans Affairs Medical Center, 500 West Fort Street,
Boise, ID 83702; 2 University of Idaho, Department of Life
Sciences, PO Box 443051, Moscow, ID 83844-305; 3 University
of Washington School of Medicine, 1959 NE Pacific
Street, Seattle WA 98195; hamilton.steph@yahoo.com).
Background: NSAIDs may worsen group A streptococcal
(GAS) disease yet some advocate NSAIDs to treat
bacterial infection. We examined the effects of selective
and non-selective NSAIDs, alone and with antibiotics, on
initiation of post-injury GAS muscle infection and on survival
of mice with GAS myonecrosis. Methods: Wild-type
or COX-2 -/- mice underwent standardized hindlimb muscle
injury. NSAIDs were given 47 hr post-injury and 1 hr prior
to IV M-type 3 GAS. GAS in muscles, blood and spleen was
quantitated 6 hrs later. In separate studies, mice were infected
IM with LD 100
GAS. NSAIDs and/or antibiotics (penicillin,
clindamycin) were given every 8-12 h for 72 hr. Survival was
followed for 14 d. Results: The non-selective NSAID significantly
increased GAS infection of injured muscle in only
wild-type mice. Pharmacologic inhibition, but not genetic
deletion, of COX-2 reduced the systemic bacterial burden
below the muscle infection threshold. In established myonecrosis,
non-selective and COX-2-selective NSAIDs significantly
accelerated the time to death and greatly reduced antibiotic
efficacy. Conclusions: We conclude that use of certain
NSAIDs, either alone or as adjuncts to traditional antibiotic
therapy, for suspected or established GAS infection is not
prudent and may, in fact, contribute to worse outcomes in
severe GAS infection.
86 Modeling HIV-1 Latency in Primary Central Memory Lymphocytes,
Laura MARTINS*, ALBERTO Bosque,
Marylinda Famigletti, Peter Ramirez,
Camille Novis, and VICENTE Planelles
(Division of Microbiology and Immunology, Department of
Pathology, University of Utah, 15N Medical Dr., Salt Lake
City, UT, 84112; laura.martins@path.utah.edu).
Central memory CD4+ T lymphocytes (T CM
) harbor the
majority of latent HIV-1 proviruses in vivo. We have developed
a latency assay based on cultured T CM
cells to characterize
biological processes important in the establishment
and maintenance of HIV-1 latency. Using this model, we
have characterized the effects of antigenic stimulation and
homeostatic proliferation induced by cytokines on the latent
reservoir. Antigenic stimulation through the TCR and the
subsequent activation of the Lck/calcineurin/NFAT pathway
reactivates virtually all latently infected cells, and successfully
depletes the reservoir, but would result in cytokine
storm if used in vivo. IL-2+IL-7 cytokine stimulation reactivates
latently infected cells, albeit infefficiently, with concomitant
expansion of the latent reservoir via homeostatic
proliferation. Because both of these options are therapeutically
untenable, we sought alternate approaches for reactivation
of latent HIV-1.
We adapted our published HIV-1 latency model for high
throughput screening of compounds with the ability to reactivate
latent HIV-1. One such compound, denoted “C7”, is
capable of viral reactivation within 80% of latently infected
cells, without global T cell activation. This result demonstrates
the existence of alternative signaling pathways leading
to activation of latent proviruses in primary cells. Key
signaling elements controlling these pathways should be
considered as novel therapeutic targets.
Recent Advances in
Pharmacology and Toxicology
Wednesday, 8:30 a.m. in PAYETTE RIVER
87 Inhibition of Growth of Cervical Cancer Cells by a
Chymotrypsin-Like Protease Inhibitor, KIMBERLY J
JURGENSEN*, KRISTIN A ECKERT, and GARY A
CLAWSON (Jake Gittlen Cancer Research Foundation,
Pennsylvania State University College of Medicine, H059,
500 University Drive, Hershey, PA 17033; kim_jduncan@
hotmail.com).
The chymotrypsin-like serine protease inhibitor, succinyl-alanine-alanine-proline-phenylalanine
chloromethyl
ketone (AAPF CMK
), has been shown to significantly inhibit
the growth of tumorigenic human papillomavirus (HPV)-
infected keratinocytes in organotypic raft cultures.. . We
hypothesized that AAPF CMK
treatment arrests the growth
of the HPV-16 infected cervical cancer cell lines, SiHa and
CaSki, by blocking the ability of the HPV-16 E6 and/or E7
oncoproteins from interacting with the tumor suppressor proteins,
p53 and pRb, respectively...The effects of AAPF CMK
treatment on cellular growth, cell cycle kinetics, DNA synthesis,
and p53 and pRb expression levels were examined in
72