University at Buffalo
The Witebsky Center

The Witebsky Center
University at Buffalo
Bacteriology hostmicrobe immunology parasitology virology bioinformatics mycology
The Witebsky Center The Witebsky Center
Michael W. Russell, Ph.D.

Michael W. Russell, Ph.D. Professor,
Departments of Microbiology & Immunology, and
Oral Biology; Witebsky Center for Microbial Pathogenesis and Immunology
Phone: (716) 829-2790
Fax: (716) 829-2748
Email: russellm@buffalo.edu

 

russell

Mucosal Immunology

I graduated in Natural Sciences (Biochemistry) from the University of Cambridge (St. John’s College), England (B.A. Hons., 1966; M.A., 1970), and in Microbiology from Reading University, England (Ph.D., 1973).  My post-doctoral work in Oral Microbiology and Immunology was carried out at Guy's Hospital Medical and Dental Schools, London, England.  In 1979 I moved to the University of Alabama at Birmingham and joined the large Mucosal Immunology group there, eventually becoming Research Professor of Microbiology.  I was elected to fellowship in the American Academy of Microbiology in 2000.  I came to UB as Professor of Microbiology & Immunology, and Oral Biology in 2000, and have served a term as Director of the Witebsky Center (2004-6).  In 2007 I received the IADR Distinguished Scientist Award for Research in Oral Biology.  Whenever I get any spare time I like to travel, watch birds, listen to classical music, or simply enjoy a decent pint, not necessarily in that order.
My research is broadly concerned with the induction and functions of both secretory and circulating IgA antibodies, the immune response against bacterial infections especially of the oral cavity and genital tract, and novel approaches to mucosal vaccine development.  We maintain that IgA antibodies are essentially anti-inflammatory, and can suppress damage to tissues arising from the inflammatory consequences of complement-dependent and opsono-phagocytic defense mechanisms.  These concepts may be applicable to infection-driven inflammatory conditions such as periodontal disease, and coupled with strategies for mucosal immunization may offer novel approaches to the treatment of human disease. 
Several years ago we developed a genetic strategy for coupling protein antigen segments to the highly immunogenic but non-toxic B subunit of cholera toxin (CTB) to make chimeric mucosal immunogens, and we have been investigating the mechanisms underlying the immune response to them.  This approach was initially developed with surface protein adhesin AgI/II of Streptococcus mutans, an antigen that I discovered (along with AgIII) while working in London on a vaccine against dental caries.  While I have maintained my interest in research towards a caries vaccine in collaboration with colleagues elsewhere, other applications of this approach to mucosal vaccine development include a vaccine against gonorrhea designed to elicit protective antibodies in the genital tract.  We were among the first to show the efficacy of intranasal immunization for eliciting mucosal antibody responses in the genital tract as well as other secretions.  In collaboration with Dr. Terry Connell, we have evaluated type II heat-labile enterotoxins as antigen-coupled delivery agents and adjuvants that have significantly different immunological properties from cholera toxin and may therefore be advantageous in vaccine development.  The mechanisms by which these enterotoxins exert their immunomodulatory effects, the regulatory mechanisms involved, and the generation of memory within the mucosal immune system are being pursued.  We are also exploring state-of-the-art imaging technology to follow the uptake of chimeric mucosal immunogens and enterotoxin adjuvants at mucosal inductive sites and characterize the antigen-presenting cells involved in the reponse to them.
We have also investigated human mucosal and systemic immune responses against Neisseria gonorrhoeae.  As a result of these studies, we hypothesized that gonococci are capable of interfering with the normal course of an immune response, which may explain the paucity of antibodies developed during human gonorrhea, and the lack of effective immunity induced by natural exposure to it.  We have found that Th17 cells are involved in the immune-inflammatory response to N. gonorrhoeae and are investigating their significance in a mouse model of this infection.  In confirmation of our earlier hypothesis, we have now found that N. gonorrhoeae suppresses Th1- and Th2-driven adaptive immune responses through a mechanism involving TGF-beta and the generation of T-regulatory cells.  In collaboration with other groups elsewhere we are also investigating possibilities for developing a mucosal vaccine against gonorrhea utilizing enterotoxins as immunomodulators or delivery agents for mucosal administration.

The Russell lab:


Weiwei Zhao, MD, PhD (Sun Yat-sen University, China)
Yingru Liu, MD, PhD (University of British Columbia, Canada)

Selected publications (out of 210):


Hajishengallis, G., Hollingshead, S.K., Koga, T., and Russell, M.W.  Mucosal immunization with a bacterial protein antigen genetically coupled to cholera toxin A2/B subunits.  J. Immunol. 154: 4322-4332 (1995).
Nikolova, E.B. and Russell, M.W.  Dual function of human IgA antibodies: inhibition of phagocytosis in circulating neutrophils and enhancement of responses in IL-8-stimulated cells.  J. Leukocyte Biol. 57: 875-882 (1995).
Russell, M.W., Moldoveanu, Z., White, P.L., Sibert, G.J., Mestecky, J., and Michalek, S.M.  Salivary, nasal, genital, and systemic antibody responses in monkeys immunized intranasally with a bacterial protein antigen and the cholera toxin B subunit.  Infect. Immun. 64: 1272-1283 (1996).
Hedges, S.R., Mayo, M.S., Mestecky, J., Hook, E.W., and Russell, M.W.  Limited local and systemic antibody responses to Neisseria gonorrhoeae during uncomplicated genital infections.  Infect. Immun. 67: 3937-3946(1999).
Martin, M.H., Metzger, D.J., Michalek, S.M., Connell, T.D. and Russell, M.W. Comparative analysis of the mucosal adjuvanticity of the type II heat-labile enterotoxins, LT-IIa and LT-IIb. Infect. Immun. 68: 281-287 (2000).
Wu, H.-Y., Abdu, S., Stinson, D. and Russell, M.W.  Generation of female genital tract antibody responses by local or central (common) mucosal immunization.  Infect. Immun. 68: 5539-5545 (2000).
Martin, M., Hajishengallis, G., Metzger, D.J., Michalek, S.M., Connell, T.D. and Russell, M.W.  Recombinant antigen-enterotoxin A2/B chimeric mucosal immunogens differentially enhance antibody responses and B7-dependent co-stimulation of T cells. Infect. Immun. 69: 252-261 (2001).
Russell, M.W. and Mestecky, J.  Humoral immune responses to microbial infections in the genital tract. Microb. Infect. 4: 667-677 (2002).
Russell, M.W.  Mucosal immunity. Chapter 5, p 64-80.  In New Bacterial Vaccines (Eds. Ellis, R.W. and Brodeur, B.R.) Eurekah.com, Georgetown TX and Kluwer Academic/Plenum, New York 2003).
Russell, M.W., Childers, N.K., Michalek, S.M., Smith, D.J., and Taubman, M.A.  A caries vaccine? The state of the science of immunization against dental caries.  Caries Res. 38: 230-235 (2004).
Hajishengallis, G., Nawar, H., Tapping, R.I., Russell, M.W., and Connell, T.D.  The type II heat-labile enterotoxins LT-IIa and LT-IIb and their respective B pentamers differentially induce and regulate cytokine production in human monocytic cells.  Infect. Immun. 72: 6351-6358 (2004).
Russell, M.W., Bobek, L.A., Brock, J.H., Hajishengallis, G., and Tenovuo, J.  Innate humoral defense factors.  Chapter 5, p 73-93.  In Mucosal Immunology, 3rd edition (Eds. Mestecky, J., Bienenstock, J., Lamm, M.E., Mayer, L., Strober, W., McGhee, J.R.) Academic Press/Elsevier, San Diego (2005).
Peppard, J.V., Kaetzel, C.S., and Russell, M.W.  Phylogeny and comparative physiology of IgA.  Chapter 11, p. 195-210.   In Mucosal Immunology, 3rd edition (Eds. Mestecky, J., Bienenstock, J., Lamm, M.E., Mayer, L., Strober, W., McGhee, J.R.) Academic Press/Elsevier, San Diego (2005).
Russell, M.W. and Kilian, M.  Biological activities of IgA.  Chapter 14, p 267-289.  In Mucosal Immunology, 3rd edition (Eds. Mestecky, J., Bienenstock, J., Lamm, M.E., Mayer, L., Strober, W., McGhee, J.R.) Academic Press/Elsevier, San Diego (2005).
Kilian, M. and Russell, M.W.  Microbial evasion of IgA functions.  Chapter 15, p. 291-303.  In Mucosal Immunology, 3rd edition (Eds. Mestecky, J., Bienenstock, J., Lamm, M.E., Mayer, L., Strober, W., McGhee, J.R.) Academic Press/Elsevier, San Diego (2005).
Russell, M.W., Sparling, P.F., Morrison, R.P., Cauci, S., Fidel, P.L., Martin, D., Hook, E.W., and Mestecky, J.  Mucosal immunology of sexually transmitted diseases.  Chapter 99, p 1693-1720.  In Mucosal Immunology, 3rd edition (Eds. Mestecky, J., Bienenstock, J., Lamm, M.E., Mayer, L., Strober, W., McGhee, J.R.) Academic Press/Elsevier, San Diego (2005).
Hajishengallis, G., Tapping, R.I., Martin, M.H., Nawar, H., Lyle, E.A., Russell, M.W., and Connell, T.D.  Toll-like receptor 2 mediates cellular activation by the B subunits of type II heat-labile enterotoxins.  Infect. Immun. 73: 1343-1349 (2005).
Arce, S., Nawar, H.F., Russell, M.W., and Connell, T.D.  Differential binding of Escherichia coli enterotoxins LT-IIa, LT-IIb and of cholera toxin elicits differences in apoptosis, proliferation, and activation of lymphoid cells.  Infect. Immun. 73: 2718-2727 (2005).
Price, G.A., Russell, M.W., and Cornelissen, C.N.  Intranasal administration of recombinant Neisseria gonorrhoeae transferrin binding proteins A and B conjugated to the cholera toxin B subunit induces systemic and vaginal antibodies in mice.  Infect. Immun. 73: 3945-3953 (2005).
Hajishengallis, G., Arce, S., Gockel, C.M., Connell, T.D., and Russell, M.W.  Immunomodulation with enterotoxins for the generation of secretory immunity or tolerance:  applications for oral infections.  J. Dent. Res. 84: 1104-1116 (2005).
Gockel, C.M. and Russell, M.W. Induction and recall of immune memory by mucosal immunization with a non-toxic recombinant enterotoxin-based chimeric protein.  Immunology 116: 477-486 (2005).
Nawar, H.F., Arce, S., Russell, M.W., and Connell, T.D.  Mutants of type II heat-labile LT-IIa with altered ganglioside-binding activities and diminished toxicities are potent mucosal adjuvants.  Infect. Immun. 75: 621-633 (2007).
Arce, S., Nawar, H.F., Muehlinghaus, G., Russell, M.W., and Connell, T.D.  In vitro induction of IgA- and IgM-secreting plasma blasts by cholera toxin depends upon T cell help and is mediated by CD154 up-regulation and inhibition of IFN-g synthesis.  Infect. Immun. 75: 1413-1423 (2007).
Price, G.A., Masri, H.P., Russell, M.W., and Cornelissen, C.N.  Gonococcal transferrin binding protein chimeras induce bactericidal and growth inhibitory antibodies in mice. Vaccine 25: 7247-7260 (2007).
Russell, M.W.  Biological functions of IgA, Chapter 6, pp 144-172.  In Mucosal Immune Defense: Immunoglobulin A (Ed. Kaetzel, C.S.), Springer, New York (2007).
Mestecky, J., Russell, M.W., and Elson, C.O.  Perspectives on mucosal vaccines: is oral tolerance a barrier?  J. Immunol. 179: 5633-5638 (2007).
Hajishengallis, G., and Russell, M.W.  Molecular approaches to vaccination against oral infections, Chapter 11, pp 257-285.  In Molecular Oral Microbiology (Ed. Rogers, A.H.), Caister Academic Press, Norfolk, U.K. (2008).
Brandtzaeg, P., Kiyono, H., Pabst, R., and Russell, M.W.  Terminology: Nomenclature of mucosa-associated lymphoid tissue.  Mucosal Immunol. 1: 31-37 (2008).
Russell, M.W. and Hook, E.W.  Gonorrhea.  Chapter 49, p. 953-971, In Vaccines for Biodefense and Emerging and Neglected Diseases (Eds. Barrett, A.D.T. and Stanberry, L.R.), Elsevier, Amsterdam/London (2009). 
Ostberg, K.L., Russell, M.W., and Murphy, T.F. Mucosal immunization of mice with recombinant OMP P2 induces antibodies that bind to surface epitopes of multiple strains of nontypeable Haemophilus influenzae.  Mucosal Immunol. 2: 63-73 (2009).
Mestecky, J. and Russell, M.W.  Specific antibody activity, glycan heterogeneity and polyreactivity contribute to the protective activity of S-IgA at mucosal surfaces.  Immunol. Lett.  124: 57-62 (2009).
Liang, S., Hosur, K.B., Nawar, H.F., Russell, M.W., Connell, T.D., and Hajishengallis, G.  In vivo and in vitro adjuvant activities of the B subunit of type IIb heat-labile enterotoxin (LT-IIb-B5) from Escherichia coli.  Vaccine 27: 4302-4308 (2009).
Feinen, B., Jerse, A.E., Gaffen, S.L., and Russell, M.W.  Critical role of Th17 responses in a murine model of Neisseria gonorrhoeae genital infection.  Mucos. Immunol. 3: 312-321 (2010).
Russell, M.W. and Mestecky, J.  Tolerance and protection against infection in the genital tract. Immunol. Invest. 39: 500-525 (2010).

Patents:
 US patent #6,030,624, 29 February 2000. “Mucosal Immunogens for Novel Vaccines”
US patent #6,846,488, 25 January 2005. “Chimeric Antigen-Enterotoxin Mucosal Immunogens”
US patents #7,455,843; 25 November 2008; and #7,776,338 B2, 17 August 2010. “Adjuvant Activities of Mutants of LT-IIa and LT-IIb Enterotoxin Lacking Binding to Ganglioside”

 

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