Daniel Kalman, PhD
Associate Professor of Pathology
Utilization of host tyrosine kinases by bacterial and viral pathogens. When I started my laboratory at Emory, I expanded on the theme of identifying host molecules used by bacteria and viruses that support pathogenesis. Retroviruses such as RSV likely incorporate cellular tyrosine kinases into their genomes through recombination with cellular genes and selection based on preferential growth of transformed cells, which led Bishop and Varmus to identify cellular Src in mammalian cells. The question we asked was whether oncogenic retroviruses were an anomaly, or whether other pathogens might also utilize tyrosine kinases or other cellular signaling molecules, perhaps even without encoding them. We reasoned that selective pressure might drive many pathogens to utilize signaling molecules in the host by evolving proteins that interface with them. In a remarkable example of evolutionary convergence, we showed that many bacterial and viral pathogens utilize host tyrosine kinases, including members of the Src and Abl families. The list includes diarrheagenic E. coli, Pseudomonas, Salmonella, Shigella, Helicobacter, and Chlamydia, amongst bacteria, and filoviruses (Ebola), Coxsackie, West Nile, Kaposi sarcoma, Polyoma and Pox amongst viruses. Our most recent work established that pathogenic mycobacteria also use Abl and related tyrosine kinases for entry and intracellular survival in macrophages. Notably, the mechanisms differ depending on the pathogen, and the host-pathogen interfaces appear somewhat indiscriminate; that is, most pathogens use multiple tyrosine kinases in a redundant fashion.
Repurposing tyrosine kinase inhibitors developed for cancer as anti-pathogen therapeutics. Based on tyrosine kinase studies we began to consider whether it might be possible to develop drugs for infectious microbes, based on targeting host molecules used during pathogenesis. The Abl tyrosine kinase inhibitor imatinib mesylate (marketed as Gleevec), developed by Brian Drucker, remains a frontline therapy for chronic myelogenous leukemia (CML). Thus, therapeutics developed to target host factors dys-regulated in cancer might be “repurposed” to treat diverse microbial and viral infections, including, for example, tuberculosis. This “host directed therapeutic (HDT)” strategy was developed by my lab and has now been validated for a variety of pathogens. For example, Gleevec and related inhibitors block release of poxviruses and Ebola in vitro. Moreover, Gleevec restricts dissemination of poxvirus and protects from an otherwise lethal infection in vivo. Perhaps most importantly, Gleevec is effective against rifampicin-resistant strains of mycobacteria in vitro and in vivo, and, when co-administered, Gleevec acts synergistically with rifampicin or rifabutin against drug-susceptible strains. We are now testing Gleevec in primate models of Mtb infection with the intent of moving the drugs into humans for testing against multi-and extensively drug resistant TB and possibly Ebola as well, as early as 2016. Because Gleevec acts in synergy with antibiotics, it may decrease the likelihood of developing resistance against a co-administered antibiotics. Indeed, with co-administration of Gleevec it may even be possible to use antibiotics against strains that are ostensibly resistant to them. Thus, co-administration of antibiotics with Gleevec may both potentiate existing drug-treatment regimens and shorten their duration, thereby mitigating compliance issues. Our most recent data indicate that Gleevec, at doses that are effective in clearing Mycobacterial infections but which are 10-fold lower than those used for cancer, mimics a physiological innate response to infection in the bone marrow, called the “ emergency response,” in which hematopoietic stem cells and multipotent progenitors expand and differentiate into mature myeloid cells that migrate to peripheral sites. Gleevec effects occur in part via partial inhibition of c-Kit, suggesting a mechanism by which c-Kit controls the earliest stages of hematopoiesis. Mimicking a physiological antimicrobial response may make Gleevec broadly useful. Accordingly, Gleevec also has efficacy against infections caused by Franciscella spp., which do not use Gleevec-sensitive tyrosine kinases for pathogenesis. These observations also raise the possibility that targeting myelopoiesis may be useful for infectious diseases and neutropenia. Based on promising results in primate TB models we have been awarded a UH2/3 grant to do additional primate work and a human trial for MDR TB.
a. Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases. Reeves PM, Bommarius B, Lebeis S, McNulty S, Christensen J, Swimm A, Chahroudi A, Chavan R, Feinberg MB, Veach D, Bornmann W, Sherman M, Kalman D. Nat Med. 2005 Jul;11(7):731-9. Epub 2005 Jun 26. Erratum in: Nat Med. 2005 Dec;11(12):1361.PMID: 15980865
b. Imatinib-sensitive tyrosine kinases regulate mycobacterial pathogenesis and represent therapeutic targets against tuberculosis.Napier RJ, Rafi W, Cheruvu M, Powell KR, Zaunbrecher MA, Bornmann W, Salgame P, Shinnick TM, Kalman D. Cell Host Microbe. 2011 Nov 17;10(5):475-85. doi: 10.1016/j.chom.2011.09.010. Erratum in: Cell Host Microbe. 2011 Dec 15;10(6):635. PMID: 22100163 PMCID: PMC3222875
c. Productive replication of Ebola virus is regulated by the c-Abl1 tyrosine kinase. García M, Cooper A, Shi W, Bornmann W, Carrion R, Kalman D, Nabel GJ. Sci Transl Med. 2012 Feb 29;4(123):123ra24. doi: 10.1126/scitranslmed.PMID 3003500.
d. Low Doses of Imatinib Induce Myelopoiesis and Enhance Host Anti-microbial Immunity. Napier RJ, Norris BA, Swimm A, Giver CR, Harris WA, Laval J, Napier BA, Patel G, Crump R, Peng Z, Bornmann W, Pulendran B, Buller RM, Weiss DS, Tirouvanziam R, Waller EK, Kalman D. PLoS Pathog. 2015 Mar 30;11(3):e1004770. PMID: 25822986 PMCID: PMC4379053
e. New tricks for old dogs: countering antibiotic resistance in tuberculosis with host-directed therapeutics. Hawn TR1, Shah JA, Kalman D. Immunol Rev. 2015 Mar;264(1):344-62 PMID: 25703571 PMCID: PMC4571192f. Back to the future: host-targeted chemotherapeutics for drug-resistant TB. Napier RJ, Shinnick TM, Kalman D. Future Microbiol. 2012 Apr;7(4):431-5. doi: 10.2217/fmb.12.19. No abstract available. PMID: 22439718
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