TLR3 is required for survival following Coxsackievirus B3 infection by driving T lymphocyte activation and polarization: The role of dendritic cells

Abstract

Type B coxsackievirus (CVB) is a common cause of acute and chronic myocarditis, meningitis and pancreatitis, often leading to heart failure and pancreatic deficiency. The polarization of CD4+ T lymphocytes and their cytokine milieu are key factors in the outcome of CVB-induced diseases. Thus, sensing the virus and driving the adaptive immune response are essential for the establishment of a protective immune response. TLR3 is a crucial virus recognition receptor that confers the host with resistance to CVB infection. In the current study, we found that TLR3 expression in dendritic cells plays a role in their activation upon CVB3 infection in vitro, as TLR3-deficient dendritic cells up-regulate CD80 and CD86 to a less degree than WT cells. Instead, they up-regulated the inhibitory molecule PD-L1 and secreted considerably lower levels of TNF-α and IL-10 and a higher level of IL-23. T lymphocyte proliferation in co-culture with CVB3-infected dendritic cells was increased by TLR3-expressing DCs and other cells. Furthermore, in the absence of TLR3, the T lymphocyte response was shifted toward a Th17 profile, which was previously reported to be deleterious for the host. TLR3-deficient mice were very susceptible to CVB3 infection, with increased pancreatic injury and extensive inflammatory infiltrate in the heart that was associated with uncontrolled viral replication. Adoptive transfer of TLR3+ dendritic cells slightly improved the survival of TLR-deficient mice following CVB3 infection. Therefore, our findings highlight the importance of TLR3 signaling in DCs and in other cells to induce activation and polarization of the CD4+ T lymphocyte response toward a Th1 profile and consequently for a better outcome of CVB3 infection. These data provide new insight into the immune-mediated mechanisms by which CVBs are recognized and cleared in order to prevent the development of myocarditis and pancreatitis and may contribute to the design of therapies for enteroviral infections.

Roles and Mechanisms of Interleukin-12 Family Members in Cardiovascular Diseases: Opportunities and Challenges

“…Just as Table 4. Although IL-12 family Fairweather et al, 2003;Yang et al, 2011;Nyland et al, 2012;Jenke et al, 2014;Kong et al, 2014;Hu et al, 2014;Zha et al, 2015;Zhang et al, 2017;Miteva et al, 2017;Sesti-Costa et al, 2017;Ouyang et al, 2017;Xu et al, 2018 Zhou et al, 2001;Kempe et al, 2009;Correia et al, 2010;Lin et al, 2012;Khojasteh-Fard et al, 2012;Jin et al, 2012;Yong et al, 2013;Chistiakov et al, 2015;Abbas et al, 2015;A Shahi et al, 2015;Zykov et al, 2016;Opstad et al, 2016;Zhu et al, 2018;Rasa et al, 2018; Lee et al, 1999;Davenport and Tipping, 2003;Hauer et al, 2005;Koltsova et al, 2012;Hirase et al, 2013;Subramanian et al, 2015;Kan et al, 2016;Tao et al, 2016;Engelbertsen et al, 2018;Fatkhullina et al, 2018;Ryu et al, 2018;Huang et al, 2019;Huang et al, 2019;Wang et al, 2019;Jia et...…”

“…Knockout of the STAT4 pathway and IFN-g can significantly reverse the protective effects of IL-12 and aggravate myocardial cell injury and mortality (Fairweather et al, 2005). Similarly, circulating IL-23 levels were also observed to be increased in coxsackievirus B3induced mouse viral myocarditis (Yang et al, 2011;Sesti-Costa et al, 2017). Although there are no direct reports concerning the effects of IL-23 on viral myocarditis, emodin can reduce myocardial injury and mortality mediated by viral myocarditis by reducing the expression of IL-23, indicating that IL-23 can aggravate myocardial injury in viral myocarditis (Jiang et al, 2014).…”

“…Aggravate Aggravate -- Zhu et al, 2013;Zhang et al, 2014b;Zhu et al, 2014;Hu et al, 2016;Liao et al, 2017; Shioi et al, 1997;Nishio et al, 2003;Fairweather et al, 2005;Yang et al, 2011;Jiang et al, 2014;Kong et al, 2014;Hu et al, 2014;Zhu et al, 2015;Sesti-Costa et al, 2017;Ouyang et al, 2017;Xu et al, 2018 Cardiomyopathy Aggravate Aggravate -- Afanasyeva et al, 2001;Fairweather et al, 2004;Sonderegger et al, 2006;Zafra et al, 2007;Chen et al, 2009;Noutsias et al, 2011;Wu et al, 2016;…”

An overview of the immune mechanisms of viral myocarditis

“…On the contrary, increased susceptibility to CVB3 myocarditis was noted in animals deficient in TLR3 and TRIF (adapter protein for TLR3), as well as MDA‐5 and mitochondrial antiviral signaling (MAVS) protein occurring in association with skewed Th2 and Th17 responses, and reduced type I IFN secretion, suggesting their importance in disease protection 56,59,62,65 . Although animals lacking complement receptor (CR)1/CR2, TRIM21 (cytosolic ubiquitin ligase), a protein that has a synergistic function with the complement system, 127 and the IFN‐stimulated ubiquitin‐like protein ISG15 showed enhanced severity of myocarditis, 67,69,71 increased myocardial damage in NLRP3‐deficient mice suggests that the NLRP3 inflammasome activation may serve a protective function in CVB3 infection 73 .…”

MiR-146a down-regulates inflammatory response by targeting TLR3 and TRAF6 in Coxsackievirus B infection

“…Aggravated inflammatory response of the CVB-infected cells damages myocardial tissues and leads to heart failure (Verma et al 2010;Yin et al 2014;Garmaroudi et al 2015). CVB also has been reported to cause a wide range of other infections such as meningitis, pancreatitis, and meningoencephalitis (Ye et al 2013;Yin et al 2014;Sesti-Costa et al 2017).…”