This week’s Medicine Grand Rounds guest lecturer was Dr. Robert Finberg, currently Chair of the Department of Medicine at the University of Massachusetts Medical School. He earned his MD from Albert Einstein College of Medicine and trained in Medicine at Bellevue Hospital starting in 1974. He was a Fellow in Infectious Diseases at Harvard Medical School, and there established a rich research career over the ensuing twenty years. Dr. Finberg’s research focuses on host-microbial interactions, defining the cell surface proteins that, like CD14 and Toll-like receptors, control host responses to pathogens. He accepted his current position as Department Chair at the University of Massachusetts in 1999. His Medicine Grand Rounds Lecture was entitled: “Innate Immunity and Viral Pathogenesis.”
Dr. Finberg began with a case vignette of an infant who was admitted to the hospital unresponsive with bleeding from the nares. The infant was found to be in septic shock from HSV-1, but the mother was HSV-1 negative. After further investigation, the father was found to have an HSV lesion on his finger, which he used to feed the infant. Why do infants die of viral sepsis, while adults rarely do? Toll-like receptors (TLRs) are part of the answer.
TLRs are a group of ancient pattern recognition proteins found in many diverse species, from lilacs to humans, and discriminate between self and non-self. In mammals, TLRs interact with products of infectious agents to activate cytokine gene transcription, thereby activating the innate immune system (macrophages, NK cells and neutrophils) which then stimulate the adaptive immune system. Mammalian TLRs were initially noted to stimulate proinflammatory cytokines (IL-1, TNF-α, and IL-6), which cause fever and septic shock during bacterial and fungal infections. TLRs were later also found to interact with viral proteins and initiate fever, and sometimes hypotension and a shock-like picture. They also regulate the production of type 1-IFNs which defend against viruses. Not surprisingly, viruses have found ways to inhibit TLR-specific responses, and the interaction between viruses and TLRs is critical in understanding viral pathogenesis and immunity.
Neonates, unlike adults who develop only localized disease, can develop a sepsis-like picture likely from activation of TLR2 on macrophages causing a “cytokine storm.” Neonates appear to have an enhanced ability to respond to TLR2 ligands, and are thus more susceptible to an overwhelming and harmful immune response. Thus, it appears that TLR activation is a “double-edged sword.”
The next logical question would be: would a TLR2 inhibitor prevent this lethal response? It is possible that a TLR2 specific inhibitor might have some effect but the response to many infections involves multiple TLRs as well as cytoplasmic DNA and RNA receptors. Along with biotechnology companies, Dr. Finberg is investigating TLR agonists, including TLR activating compounds, to increase viral-specific immunity and as vaccine adjuvants.
Perhaps TLR inhibitors can be designed to dull the sword edge that occurs with viral hemorrhagic fever and causes damage in viral encephalitis, yet preserve the edge that is an ancient defender against microbial invaders.
Finberg RW, Wang JP, Kurt-Jones EA. Toll like receptors and viruses. Rev Med Virol. 2007;17:35-43.