Office: (859) 323-5043
Fax: (859) 323-1020
Lab: (859) 323-9547
Beth A. Garvy, Ph.D.
Professor and Chair
Doctoral Studies: Michigan State University.
Postdoctoral: University of Miami Medical School and Trudeau Institute.
Pneumocystis carinii is an opportunistic fungal pathogen that can cause pneumonia in immunosuppressed individuals including AIDS patients. It has been known for a number of years that an intact CD4 T cell compartment is critical for defense against P. carinii. However, there are a number of questions regarding the immune response to P. carinii that are still unresolved. The focus of our work is to examine the immune response to P. carinii using a murine model of infection. There are two major questions that are being addressed:
1. What is the role of B cells in the immune response to P. carinii? It has not been fully appreciated that B cell function is as critical to host defense against P. carinii as is CD4 T cell function. Mice that are deficient in B cells but have normal T cells will succumb to P. carinii pneumonia. Clearly there is a role for P.carinii-specific antibody in clearance of the infection. However, B cells have a variety other of functions such as cytokine production and antigen presentation. We have been using a chimeric mouse model in which we generate mice that have a deficiency in a specific molecule on B cells. We have determined that MHC class II must be present on B cells for clearance of P. carinii. In addition, expression of CD40 on B cells is also required for clearance of the infection. Interestingly, neither MHC class II nor CD40 deficient chimeras were able to produce P. carinii-specific IgG. We are currently using a chimeras, adoptive transfers, and transgenic mice to determine whether B cells are required during early T cell priming events or whether the downstream production of IgG is the major role of B cells in resisting P. carinii infection.
2. How do neonatal mice handle respiratory infection? It has long been known that infants are particularly susceptible to respiratory pathogens. We are using mouse models of P. carinii and influenza virus infection to examine neonatal immunity in the lungs. Interestingly, mice infected as neonates take three weeks to mount an inflammatory response to P. carinii whereas adult mice given a comparable infectious dose respond within 3-5 days and clear the infection within 2-3 weeks. We have found that T cells isolated from neonatal mice are able to effect clearance of P. carinii when transferred to an adult lung environment. This has led us to more closely scrutinize the neonatal lung environment. We have found that proinflammatory cytokines and chemokines are deficient in neonatal lungs however TGFβ and IL-10, both anti-inflammatory, are elevated. In addition, dendritic cells in neonatal lungs do not mature and migrate to draining lymph nodes with the same efficiency as dendritic cells in adult lungs. Interestingly, neonatal mice develop interstitial pneumonia in response to influenza virus infection which may be one reason why they are significantly more susceptible to infection than are adult mice. Neonatal mice mount a significantly different chemokine and cytokine response to influenza virus infection. Additionally, the response to immunodominant influenza epitopes is significantly different in neonatal mice. We are currently utilizing transgenic and knockout mouse models to address the mechanisms responsible for these observations.
NIH R01 PI
Role of B cells in host defense against Pneumocystis
12/1/07 to 11/30/12
NIH R01 PI
Host Response to P. carinii in Neonatal Mice
7/17/2009 to 6/30/2014
Pfizer, Inc. co-I (Feola PI)
Linezolid’s impact upon immune hyporesponsiveness after influenza virus infection
11/1/2010 to 12/30/2011
Selected Recent Publications:
Fallah M.P., Chelvarajan R.L., Garvy B.A., and S. Bondada. (2011) Role of phosphoinositide 3-kinase-Akt signaling pathway in the age-related cytokine dysregulation in splenic macrophages stimulated via TLR-2 or TLR-4 receptors. Mech Ageing Dev. [Epub ahead of print]
Lines J.L., Hoskins S., Hollifield M., Cauley L.S., and B.A. Garvy. (2010) The migration of T cells in response to influenza virus is altered in neonatal mice. J Immunol. 185(5):2980-8.
Feola D.J., Garvy B.A., Cory T.J., Birket S.E., Hoy H., Hayes Jr. D., and B.S. Murphy. (2010) Azithromycin alters macrophage phenotype and pulmonary compartmentalization during lung infection with Pseudomonas. Antimicrob Agents Chemother. 54(6):2437-47. PDF
Oakley O.R., Garvy B.A., Humphreys S., Qureshi M.H., and C. Pomeroy. (2008) Increased weight loss with reduced viral replication in interleukin-10 knock-out mice infected with murine cytomegalovirus. Clin Exp Immunol. 151(1):155-64. PDF
Murphy B.S., Wulff C.R., Garvy B.A., and S.C. Straley. (2007) Yersinia pestis YadC: a novel vaccine candidate against plague. Adv Exp Med Biol. 603:400-14.
Feola D.J., Garvy B.A., Rapp R.P., and A.C. Thornton. (2007) Blunted humoral response to influenza vaccination in patients exposed to zidovudine plus trimethoprim-sulfamethoxazole. Pharmacotherapy. 27(7):937-47.
Hollifield, M., W.J.S. deVilliers, and B.A. Garvy. (2007) Scavenger receptor A dampens induction of inflammation in response to the fungal pathogen Pneumocystis carinii. Infect. Immun. 75:3999-4005. PDF
Empey, K.M., M. Hollifield, and B.A. Garvy. (2007) LPS stimulates alveolar macrophages resulting in reduced Pneumocystis lung burden in infant mice. Infect. Immun. 75: 3382-3393. PDF
Lund, F.E., M. Hollifield, K. Schuer, T.D. Randall, and B.A. Garvy. (2006) B cells are required for priming of CD4 cells in response to Pneumocystis lung infection. J. Immunol., 176. PDF
Feola, D.J. and B.A. Garvy (2006) Combination exposure to zidovudine plus sulfamethoxazole-trimethoprim diminishes B lymphocyte immune responses to Pneumocystis murina infection in normal mice. Clin. Vaccine Immunol., 13:193-201.
Feola, D.J. and B.A. Garvy. (2005) Zidovudine plus sulfamethoxazole- trimethoprim adversely affects B lymphocyte maturation in bone marrow of normal mice. Int. Immunopharmacol., 5:1881-1894.
Qureshi, M.H., K.M. Empey, and B.A. Garvy. (2005) Modulation of proinflammatory responses to Pneumocystis carinii f. sp. muris in neonatal mice by granulocyte-macrophage colony-stimulating factor and IL-4: role of APCs. J. Immunol. 174,441.
Empey, K. M., M. Hollifield, K. Schuer, F. Gigliotti, and B.A. Garvy. (2004) Passive immunization of neonatal mice against Pneumocystis carinii f. sp. muris enhances control of infection without stimulating inflammation. Infect. Immun. 72,6211.
Lund, F.E., K. Schuer, M. Hollifield, T.D. Randall and B.A. Garvy. (2003) Clearance of Pneumocystis carinii in mice is dependent on B cells but not on P. carinii-specific antibody. J. Immunol. 171, 1423. PDF
Qureshi, M.H., A.G. Harmsen, and B.A. Garvy. (2003) IL-10 Modulates Host Responses and Lung Damage Induced by Pneumocystis carinii Infection. J. Immunol. 170, 1002. PDF
Partida-Sanchez, S., D. Cockayne, S. Monard, E.L. Jacobson, B. Garvy, K. Kusser, M. Howard, A. Harmsen, T.D. Randall, and F.E. Lund (2001) Cyclic ADP-ribose production by CD38 controls extracellular calcium influx and chemtaxis in neutrophils and is required for bacterial clearance in vivo. Nature Med. 7,1209. PDF
Qureshi, M.H. and B.A. Garvy (2001) Neonatal T cells in an adult lung environment are competent to resolve Pneumocystis carinii pneumonia. J. Immunol. 166, 5704. PDF
Garvy, B.A. and M.H. Qureshi (2000) Delayed inflammatory response to Pneumocystis carinii infection in neonatal mice is due to an inadequate lung environment. J. Immunol. 165, 6480. PDF