David Irani, M.D.
David N. Irani (M.D. 1987) is an Associate Professor in the Department of Neurology at the University of Michigan Medical School.
Dr. Irani returned to UM in July 2007 after spending nearly 15 years on the faculty at the Johns Hopkins University School of Medicine (Neurology) and Bloomberg School of Public Health (Molecular Microbiology and Immunology). There he served as an attending physician in the Multiple Sclerosis Clinic, as co-director of the Transverse Myelitis Center, and as director of Ambulatory Services in the Department of Neurology.
Dr. Irani is a longtime resident of Ann Arbor, having been born and raised here. After earning a Bachelor of Science degree in Biomedical Sciences from UM in 1985, he went on to receive his Doctor of Medicine degree here in 1987. He then completed his internship in Internal Medicine at St. Joseph Mercy Hospital in Ann Arbor in 1988, and his residency in Adult Neurology in 1993 at the Johns Hopkins Hospital in Baltimore, Maryland. He was appointed Chief Resident in Neurology in his final year of residency training.
Recipient of the Sandoz Award for excellence in the basic and clinical neurosciences from UM in 1987, Dr. Irani was honored with several awards during his tenure at Johns Hopkins. In 1993, he received the Thomas J. Preziosi Award for clinical excellence among graduating senior Neurology house officers, and in 1999, he was bestowed the Frank R. Ford Award for excellence in clinical teaching in Neurology.
He is a member of the American Academy of Neurology, the American Association of Immunologists, the International Society for Neurovirology, and an elected member of the American Neurological Association.
Ongoing work in the Irani Lab focuses on the immunopathogenesis of acute alphavirus infection of the central nervous system (CNS). These pathogens are transmitted to mammalian hosts by mosquito vectors, often resulting in devastating neurological damage once CNS spread occurs. Using a mouse model of acute alphavirus encephalomyelitis (brain and spinal cord infection), we have uncovered an important contribution of the innate immune response arising from activated microglial cells, the endogenous myeloid cell population of the CNS, in disease pathogenesis. Through multiple direct and indirect injury mechanisms, these cells contribute to neuronal damage and fatal outcome in infected animals. As a result, interventions that target these host responses may provide an important therapeutic strategy for this disease and related infections that occur in humans.
Ongoing Projects in the Irani Lab
1) Role of Pattern-Recognition Receptors and Innate Immunity in the CNS During Acute Viral Encephalitis
Microglia are the main endogenous myeloid cell population of the CNS. While these cells provide important beneficial immune functions during local immune responses within the brain, their aberrant or prolonged activation can result in neurodegeneration. Using a mouse model of acute alphavirus encephalitis, we have found that locally activated microglial cells facilitate neuronal injury through multiple mechanisms. How these cells become activated, however, is presently unknown. We hypothesize that signals arising from virus-infected neurons, either cellular or viral in origin, activate microglia via known pattern-recognition receptors (PRRs) to trigger pathogenic host responses. A combination of in vitro techniques and in vivo viral challenges of various PRR-deficient animals can be pursued to test this hypothesis.
2) Immune Mechanisms of Neuronal Injury in the CNS During Experimental Viral Encephalitis
Acute viral infection of the CNS causes substantial morbidity and mortality via direct viral damage of neurons, but we have recently determined that there is substantial bystander injury to uninfected neurons as well. Host responses arising from activated microglial cells are implicated in this bystander neuronal injury, although little is known about the immunological mechanisms underlying this cellular damage. We hypothesize that inflammatory mediators, including but not limited to nitric oxide, proinflammatory cytokines, and reactive oxygen species, are produced by activated microglia to directly or indirectly damage neurons. Successful progress towards addressing this hypothesis will likely require the use of various in vivo and ex vivo analysis methodologies to implicate individual inflammatory mediators in this aspect of disease pathogenesis.
3) Role of Astrocytes in Neuronal Dysfunction and Injury During CNS Inflammation
Astrocytes are essential for CNS homeostasis and neuronal function. They are also well equipped to survive and function in the milieu of the inflamed CNS. During virus-induced neuroinflammation, astrocytes lose their capacity to take up the excitatory neurotransmitter, glutamate, causing neuronal cell death. In relapsing experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS), astrocyte support of neuronal synapses becomes defective causing reversible neurological deficits. Both glutamate transporters and synaptogenic proteins produced by astrocytes appears to be directly influenced by the local inflammation. Ongoing studies aim to characterize the molecular mechanisms underlying these events with an eye towards developing novel therapies that prevent or reverse neuronal damage in these diseases.
Esen N, Rainey-Barger EK, Huber AK, Blakely PK, Irani DN. Type-I interferons suppress microglial production of the lymphoid chemokine, CXCL13. GLIA 2014 May 14. doi:10.1002/glia.22692. [Epub ahead of print]
Esen N, Blakely PK, Rainey-Barger EK, Irani DN. Complexity of the microglial activation pathways that drive innate host responses during lethal alphavirus encephalitis in mice. ASN NEURO 2012:4(4):art:e0000x.doi:10.1042/AN20120016 PMCID: PMC3342594.
Rainey-Barger EK, Blakely PK, Huber AK, Segal BM, Irani DN. Virus-induced CD8+ T cells accelerate the onset of experimental autoimmune encephalomyelitis: implications for how viral infections might trigger multiple sclerosis exacerbations. J Neuroimmunol 2012;259:47-54. PMCID: PMC3654028
Rainey-Barger EK, Rumble JM, Lalor SJ, Esen N, Segal BM, Irani DN. The lymphoid chemokine, CXCL13, is dispensable for the initial recruitment of B cells to the acutely inflamed central nervous system. Brain Behav Immun 2011;25:922-931.
Blakely P, Kleinschmidt-DeMasters BK, Tyler KL, Irani DN. Disrupted glutamate transporter expression in the spinal cord with acute flaccid paralysis due to West Nile Virus infection. J Neuropathol Exp Neurol 2009;68:1061-1072.
Prow NA, Irani DN. The inflammatory cytokine, interleukin-1 beta, mediates loss of astroglial glutamate transport and drives excitotoxic motor neuron injury in the spinal cord during acute viral encephalomyelitis. J Neurochem 2008;105:1276-1286.
Irani DN, Prow NA. Neuroprotective interventions targeting detrimental host immune responses protect mice from fatal alphavirus encephalitis. J Neuropathol Exp Neurol 2007;66:533-544.
Prow NA, Irani DN. The opioid receptor antagonist, naloxone, protects spinal motor neurons in a murine model of alphavirus encephalomyelitis. Exp Neurol 2007;205:461-470.
Darman J, Backovic S, Dike S, Maragakis NJ, Krishnan C, Rothstein JD, Irani DN* , Kerr DA*. Viral-induced spinal motor neuron death is non-cell-autonomous and involves glutamate neurotoxicity. J Neurosci 2004;24:7566-7575 (*co-corresponding authors).
Nargi-Aizenman JL, Havert MB, Zhang M, Irani DN, Rothstein JD, Griffin DE. Neural degeneration, paralysis and death due to acute viral encephalomyelitis are prevented by glutamate receptor antagonists. Ann Neurol 2004;55:541-549.
Kerr DA, Larsen T, Cook SH, Fannjiang Y-R, Choi E, Griffin DE , Hardwick JM, Irani DN. BCL-2 and BAX protect adult mice from lethal Sindbis virus infection but do not protect spinal motor neurons or prevent paralysis. J Virol 2002;76:10393-10400.
Havert MB , Schofield B, Griffin DE , Irani DN. Activation of divergent neuronal cell death pathways in different target cell populations during neuroadapted Sindbis virus infection of mice. J Virol 2000;74:5352-5356.