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Alan S. Cross, MD

Academic Title:

Professor

Primary Appointment:

Medicine

Location:

HSF1, Room 480

Phone (Primary):

(410) 706-5328

Phone (Secondary):

(410) 706-6499

Fax:

(410) 706-6205

Education and Training

Harvard College (magna cum laude), B.A., 1966

University of Pennsylvania School of Medicine, M.D., 1970

Post-graduate Training

  • Presbyterian St. Luke's Hospital, Medicine, 1971-1972
  • Harvard Medical Service, Boston City Hospital, Medicine, 1972-1973
  • University of Rochester School of Medicine, Strong Memorial Hospital, Infectious Diseases/Medicine, 1973-1974
  • Walter Reed Army Institute of Research, 1974-1975

Biosketch

Dr. Cross is Professor of Medicine at the Center for Vaccine Development and Global Health (CVD). He is trained in internal medicine and infectious diseases and has been a physician-scientist, with a primary interest in vaccine development, for over 40 years. Dr. Cross develops conjugate vaccines to prevent infection and colonization from Gram-negative bacteria including Pseudomonas aeruginosa, Klebsiella, and E. coli.

Dr. Cross served in the U.S. Army at the Walter Reed Army Institute of Research for 20 years and was head of the Hospital Epidemiology Unit at Walter Reed Army Hospital. During his service, he developed a detoxified endotoxin subunit vaccine and vaccines for Pseudomonas aeruginosa, Klebsiella, and E. coli that progressed to Phase 3 clinical studies. As Chief of the Department of Bacterial Diseases, he directed clinical studies on meningococcal and gonococcal infections and research on biodefense.

After his retirement from the Army in 1994, he became Director of the Program in Infectious Diseases at the University of Maryland Greenebaum Cancer Center and member of the attending staff of the Division of Infectious Diseases. In 2003, he joined the CVD. In response to bioterrorism, the National Institutes of Health (NIH) created the Middle Atlantic Regional Centers of Excellence (MARCE) where Dr. Cross was co-leader of the Tularemia and later Mucosal Biology Research Programs.

Dr. Cross has served two rotations on the Anti-infective Drug Advisory Committee of the U.S. Food and Drug Administration (FDA), numerous special emphasis panels and a permanent study section for the NIAID and Department of Defense, an advisory committee for meningococcal vaccines at the Walter Reed Army Institute of Research, and on many data safety and monitoring committees for clinical studies sponsored by industry and the National Institutes of Health (NIH).

Research/Clinical Keywords

Gram-negative bacteria, vaccines, CD28/B-7 immunosynapse, glycobiology, immune response, biodefense,

Highlighted Publications

Dr. Cross has authored 203 peer-reviewed papers, 221 abstracts, 44 book chapters and has been issued 8 patents for his discoveries.

A complete list of published work is available in MyBibliography.

Cross AS, Greenberg N, Billington M, Zhang L, DeFilippi C, May RC, Bajwa KK. Phase 1 testing of detoxified LPS/group B meningococcal outer membrane protein vaccine with and without synthetic CPG 7909 adjuvant for the prevention and treatment of sepsis. Vaccine. 2015 Nov 27;33(48):6719-26. doi: 10.1016/j.vaccine.2015.10.072.

Kang TJ, Basu S, Zhang L, Thomas K, Vogel S, Baillie L, Cross A. Bacillus anthracis spores and lethal toxin induce IL-1beta via functionally distinct signaling pathways.. Eur J Immunol. 2008;38:1574-1584. (Featured article)

Harris KM, Ramachandran G, Basu S, Rollins S, Mann D, Cross AS. The IL-23/Th17 axis is involved in the adaptive immune response to B. anthracis in humans. Eur J Immunol. 2014;44(3):752-62.

Ramachandran G, Tulapurkar ME2, Harris KM, Arad G, Shirvan A, Shemesh R, DeTolla LJ, Benazzi C, Opal SM, Kaempfer R, Cross AS. A peptide antagonist of CD28 signaling attenuates toxic shock and necrotizing soft tissue infection induced by Streptococcus pyogenes. J Infect Dis. 2013 Jun 15; 207(12):1869-1877.

Ramachandran G, Kaempfer R, Chung C-S, Shirvan A, Chahin AB, Palardy JE, Parejo NA, Chen Y, Whitford M, Arad G, Hillman D, Shemesh R, Ayala A, Cross AS, Opal SM. CD28 homodimer interface mimetic peptide acts as a preventive and therapeutic agent in models of severe bacterial sepsis and Gram-negative bacterial peritonitis. J Infect Dis. 2015;211:995-1003.

Additional Publication Citations

Cross AS, Sadoff JC, Kelly N, Bernton E, Gemski P. Pretreatment with recombinant murine tumor necrosis factor/cachectin and murine interleukin-1 alpha protects mice from lethal bacterial infection. J Exp Med. 1989;169:2021-2027.

Feng C, Zhang L, Almulki L, Faez S, Whitford M, Hafezi-Moghadam A, Cross AS. Endogenous PMN sialidase activity exposes activation epitope on CD11b/CD18 which enhances its binding interaction with ICAM-1. J Leukoc Biol. 2011;90:313-321.

Feng C, Stamatos NM, Dragan A, Medvedev A, Whitford M, Zhang L, Song C, Rallabhandi P, Nhu Q, Vogel SN, Geddes C, Cross AS. Sialyl residues modulate LPS-mediated signaling through the Toll-like receptor 4 complex. PLoS One. 2012;7:e32359.

Stamatos NM, Gomatos PJ, Cox J, Nelson S, Fowler A, Dow N, Wohlhieter JA, Cross AS. Desialylation of peripheral blood mononuclear cells promotes growth of HIV-1. Virology. 1997;228:123-131.

Cross AS and Wright DG. The mobilization of sialidase from intracellular stores to the surface of human neutrophils and its role in stimulated adhesion responses of these cells. J Clin Invest. 1991 Dec;88:2067-2076.

Research Interests

Major research interests of the Cross laboratory include:

  1. Development of vaccines for gram-negative bacterial infections
  2. Characterization of the novel CD28/B-7 immunosynapse
  3. Role of glycobiology in the innate immune response
  4. Biodefense

Dr. Cross developed a detoxified endotoxin vaccine that elicited antibodies to a highly conserved region of lipopolysaccharide (LPS) that induced active and passive protection against heterologous Gram-negative bacteria (GNB) in multiple animal models of sepsis; his work progressed to two Phase 1 clinical trials. The vaccine also elicited anti-endotoxin antibodies in bovine serum and colostrum, with the latter protecting from lethal endotoxemia in animal models of “leaky gut.” This approach may be of utility in HIV infection, inflammatory bowel disease, and as surgical prophylaxis. Our earlier O-typing of bacteremic Pseudomonas (PA) and Klebsiella (KP) strains is being used to develop novel KP and PA vaccines for the prevention/treatment of bacteria that cause multi-antibiotic resistant infections.

Dr. Cross pioneered the study of the role of glycosylation, particularly sialic acid (SA), in modulating in the innate immune response. He showed that removal of SA residues from beta 2-integrin or Toll-like receptor 4 by exogenous (e.g. influenza virus) or endogenous sialidase primes the innate immune response. He later showed that desialylation of endothelial cells increased PMN adherence and altered CD31 function, desialylation of dendritic cells enhanced cytokine expression, and that epithelial cell  sialidases regulate the activity of MUC1 and EGFR. He was among the first to show the importance of sialic acid in HIV infectivity. More recently, he demonstrated in vivo the importance of sialidases and galectins in acute lung injury and influenza infection.

His recent collaboration with the Kaempfer laboratory in Israel established that the CD28/B7 immunosynapse may be a novel target that ameliorates, but not ablates, the initiation of cytokine storms associated with a diverse range of microbial infections. Treatment with CD28 and/or B7 mimetic peptides may modulate lethal shock caused by Gram-positive bacteria and their superantigen toxins, as well as by GNB and their endotoxin (LPS). These preclinical studies led to a Phase 1 study to establish the safety of the Kaempfer lead peptide mimetic, a recently published Phase 2a multicenter study in patients admitted to trauma centers with suspected necrotizing soft tissue infection and a Phase 3 clinical trial. This approach may lead to host-directed interventions that may be initiated before a specific pathogen is identified.

Dr. Cross's research on the pathogenesis of B. anthracis (BA) infections defined novel mechanisms by which the host fights BA infection, including the role of the BA exosporium. Mice lacking genes in the autophagy pathway were markedly more susceptible to BA infection, as were mice lacking RNAse-L, until now, considered uniquely an antiviral mediator. We reported BA induced a protective caspase-1 mediated protective response via IFN-β pathway, while the LT induced caspase-1 mediated pyroptotic death via a IFN-β-independent pathway. Importantly, he observed that BA-induced IL-1β initiates a Th17 response via its induction of IL-23. He found that in patients with cutaneous anthrax antibody to LF is the earliest manifestation.

Clinical Specialty Details

Infectious Diseases

Awards and Affiliations

2010: Committee Member, National Academy of Sciences

  • Examined the Special Immunizations Program for Biodefense, a program that has provided vaccines for laboratory workers.

2010: Fellow, Infectious Diseases Society of America

2010: Fellow, American Academy of Microbiology

2008-2010: President, International Endotoxin and Innate Immunity Society

2006: International Endotoxin and Innate Immunity Society, Honorary Lifetime Membership in Recognition of Outstanding Achievement in Endotoxin Research

1994: Legion of Merit

1991: E. Karl Bastress Award for Excellence in Leveraging the Army Research and Development Program

1989: Meritorious Service Medal

Lab Techniques and Equipment

Animal models of disseminated infection; functional antibody responses; studies with primary human phagocytes; glycobiology techniques.