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Research Interests
- Role of innate immunity in regulating development of inflammatory heart disease
- Role of sex hormones in inflammatory heart disease
- What determines susceptibility to chronic heart disease and dilated cardiomyopathy (collaboration with Noel Rose)
- Role of toxins / toxicants in the development of inflammatory heart disease
- Can mercury exacerbate heart disease? (collaboration with Ellen Silbergeld)
- Role of Nrf2 and oxidative stress in heart disease (collaboration with Shyam Biswal)
Grants:
R01 HL087033
Fairweather, DeLisa (P.I.) | 01/01/07-12/31/11
NIH, NHLBI
Regulating heart disease: the adjuvant effect of viral infection.
The goal of this project is to determine the mechanisms involved in the adjuvant effect of viral infection during innate immunity and its role in regulating the development of heart disease.
Faculty Innovation Fund
BSPH | Fairweather, DeLisa (P.I.) | 05/01/07-06/30/08
A coxsackievirus-induced model of atherosclerosis.
The goal of this project is to determine whether coxsackievirus infection increases vascular inflammation and plaque formation using the apolipoprotein E deficient mouse model of atherosclerosis.
Johns Hopkins Center in Urban Environmental Health Pilot Project
P30 ES03819 | Fairweather, DeLisa (P.I.) | 06/01/07-05/31/08
NIH, NIEHS
Effect of particulate matter on cardiac mast cells and heart disease.
The goal of this project is to determine the effect of urban airborne particulate matter collected from Baltimore city on cardiac mast cells in coxsackievirus-induced acute and chronic heart disease.
More detail:
CVB3-induced myocarditis: Cardiovascular disease is the number one killer in the US and worldwide. Although the true incidence of inflammation in the heart, or myocarditis, is unknown, it is estimated that 1 in 4 individuals in the US have some form of inflammatory heart disease. Acute myocarditis is a principal cause of heart failure in young adults often progressing to chronic myocarditis, dilated cardiomyopathy (DCM) and congestive heart failure requiring heart transplantation. Coxsackievirus B3 (CVB3) infection is believed to be a principle etiologic agent in human myocarditis. In our model of CVB3-induced myocarditis, intraperitoneal (ip) infection of BALB/c mice with CVB3 results in a disease similar to that observed in humans, with the development of acute myocarditis from days 7 to 14 post infection (pi) that progresses to chronic myocarditis and DCM from day 28 to at least day 56 pi. Proinflammatory cytokines are critical for the development of myocarditis. Administration of tumor necrosis factor (TNF)- a or interleukin (IL)-1 b during the innate immune response to viral infection increases myocarditis in BALB/c and C57BL/6 strains of mice, while Toll-like receptor (TLR)4 deficient mice have significantly reduced inflammation and reduced IL-1 b and IL-18 levels in the heart during acute myocarditis.
Sex differences in heart disease: The incidence and severity of heart disease, including myocarditis, is higher among men. Women are known to have increased B cell activation and antibody levels in response to antigen or infection, indicative of a T helper (Th)2-type, IL-4 response. The lower incidence of heart disease in women has been attributed to the cardioprotective effects of estrogen. However, recent clinical trials of hormone replacement therapy found an increased risk of heart disease with estrogen and progestin treatment, indicating that many of the effects of sex hormones on the pathogenesis of heart disease remain unclear. In preliminary experiments we found that gonadectomy of male or female mice reduces CVB3-induced myocarditis, indicating that both testosterone and estrogen can increase myocarditis. These findings suggest that factors other than sex hormones contribute to differences in the severity of inflammatory heart disease observed between sexes.
Innate immunity: Recent evidence suggests a link between infections, TLR signaling and increased heart disease. TLR are a family of pattern-recognition receptors that recognize structural components shared by bacteria, viruses or fungi. TLR4 signaling is stimulated not only by bacterial LPS but also by a number of viruses including respiratory syncytial virus (RSV), mouse mammary tumor virus (MMTV) and CVB3. TLR4, TLR7 and TLR8 have recently been shown to be upregulated on human cardiac myocytes/ tissues after CVB3 infection. TLR activation results in the engagement of signaling intermediates, such as myeloid differentiation factor-88 (MyD88), Toll receptor-associated molecule (TRAM), and Toll receptor-associated activator of interferon (TRIF). Activation of caspase-1 by TLR4-mediated signaling results in production of active IL-1 b and IL-18. IL-1R or IL-18R signaling further stimulates the MyD88 pathway. The significance of TLR in activating the adaptive immune response is well established, although the precise mechanisms are still being worked out. TLR-mediated activation of antigen presenting cells (APC) such as macrophages (Mac) and dendritic cells (DC) is crucial in linking the innate and adaptive immune response following infection. Interestingly, engagement of TLR generally results in the development of a Th1-type, IFN- g response.
Recent novel findings:
1) We have found that male BALB/c mice, which develop increased acute and chronic myocarditis, have elevated numbers of mast cells (MC) expressing TLR4, MHC class II (MHCII), the costimulatory markers CD80/ CD86, and increased IL-1 b levels 6 hours (h) after infection indicating that MC may act as APC following CVB3 infection.
2) T-cell Ig mucin (Tim)-3 signaling inhibits Th1-type inflammatory responses during adaptive immunity. We found that blocking Tim-3 expressed on MC and Mac decreases CD80 expression and intracellular CTLA-4 levels (transcription factor involved in Foxp3 expression and regulatory T cell (Treg) development) during the innate immune response to CVB3 infection, resulting in reduced Treg and increased acute myocarditis (Cutting Edge J. Immunol. In press.). Thus, regulation of acute inflammation by Tim-3 begins during the innate immune response to CVB3 infection.
3) We have found that TLR4 deficient mice have significantly reduced acute myocarditis and IL-1 b and IL-18 levels in the heart and increased levels of Tim-3, indicating that TLR4 signaling reduces Tim-3 expression following CVB3 infectionresulting in increased inflammation in the heart.
4) Blocking Tim-3 during the innate immune response to CVB3 infection increases TLR4 expression on APC, indicating that Tim-3 signaling reduces TLR4expression on APC following CVB3 infection.
Balance between regulation by Tim-3 and increased inflammation by TLR4. Expression of TLR4 and Tim-3 are increased on APC following CVB3 infection. Increased expression of Tim-3 on APC or T cells in females reduces TLR4 levels and keeps inflammation in-check by increasing CTLA-4 and Treg. If TLR4 levels are elevated due to increased expression of TLR4 and/ or increased numbers of cells expressing TLR4, as occurs in males, then TLR4 downregulates Tim-3 levels resulting in reduced regulation of inflammation following infection and increased myocarditis. These findings provide a novel mechanism to explain the increased heart disease observed in males.
Proposed mechanisms leading to increased inflammation in males. TLR4 signaling following CVB3 infection increases the proinflammatory cytokines IL-1 b and IL-18 and activates CD4 + T cells via CD86 and CD28 interactions resulting in increased inflammation in the heart. Decreased levels of Tim-3 during antigen presentation reduce CD80 levels and CTLA-4 signaling resulting in lower levels of Foxp3 + Treg cells in the heart during acute myocarditis, and reduced control of inflammation. When TLR4 signaling is reduced (in TLR4-/- mice) Tim-3 levels increase, while if Tim-3 is blocked (using Tim-3R specific antibody) TLR4 levels increase. These findings show that cross-regulation by TLR4 and Tim-3 occurs during the innate immune response. Thus, increased TLR4 signaling in males results in increased inflammation in the heart and reduced regulation by Treg cells.
Related publications:
Frisancho-Kiss, S., S. E. Davis, J. F. Nyland, J. A. Frisancho, D. Cihakova, N. R. Rose, and D. Fairweather. 2007. Cutting Edge: Cross-regulation by TLR4 and T cell Ig mucin-3 determines sex differences in inflammatory heart disease. J. Immunol. Jun 1; 178(11): 6710-6714.
Frisancho-Kiss, S., J. F. Nyland, S. E. Davis, J. A. Frisancho, M. A. Barrett, N. R. Rose, and D. Fairweather. 2006. Sex differences in coxsackievirus B3-induced myocarditis: IL-12Rß1 signaling and IFN-γ increase inflammation in males independent from STAT4. Brain Res. Dec 18; 1126(1): 139-147.
Frisancho-Kiss, S., J. F. Nyland, S. E. Davis, M. A. Barrett, S. J. L. Gatewood, D. B. Njoku, D. Cihakova, E. K. Silbergeld, N. R. Rose, and D. Fairweather. 2006. Cutting Edge: T cell Ig mucin-3 reduces inflammatory heart disease by increasing CTLA-4 during innate immunity. J. Immunol. Jun 1; 176(11): 6411-6415.
Fairweather, D., S. Frisancho-Kiss, and N. R. Rose. 2005. Viruses as adjuvants for autoimmunity: evidence from coxsackievirus-induced myocarditis. Rev. Med. Virol. Jan-Feb; 15(1): 17-27.
Fairweather, D., and N. R. Rose. 2004. Women and autoimmune diseases. Emerg. Infect. Dis. Nov; 10(11): 2005-2011.
Fairweather, D., S. Yusung, S. Frisancho(-Kiss), M. Barrett, S. Gatewood, R. Steele, and N. R. Rose. 2003. IL-12Rß1 and TLR4 increase IL-1 and IL-18-associated myocarditis and coxsackievirus replication. J. Immunol. May 1; 170(9): 4731-4737.
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