Role of coxsackie‐adenovirus receptor in cardiac development and pathogenesis of congenital heart disease

Sharma, Vipul; Perry, Daniel J.; Eghtesady, Pirooz

doi:10.1002/bdr2.1860

Cited by 4 publications

(5 citation statements)

References 67 publications

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“…Epidemiologic studies done in the 1960s suggested an association between maternal enteroviral infection, particularly coxsackievirus B (CVB), and CHD [ 11 ]. Interestingly, the coxsackievirus and adenovirus receptor (CAR), through which CVB infects cardiomyocytes in myocarditis, is highly expressed in the developing heart and brain, playing a critical role in cardiac development during gestation [ 12 – 15 ].…”

Section: Introductionmentioning

confidence: 99%

Possible Association of Pulmonary Atresia with In-Utero Coxsackievirus B Exposure

et al. 2022

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Gestational viral infection has been associated with congenital heart disease (CHD). Few studies, however, have studied the potential role of gestational Coxsackievirus B (CVB) exposure in the pathogenesis of CHD. We prospectively enrolled women with pregnancies affected by CHD to explore possible associations with in utero CVB exposure. Serum samples were obtained from 122 women referred for fetal echocardiography between 2006 and 2018. We quantified CVB IgG and IgM levels, with titers ≥ 15.0 U/mL considered positive and measured neutralizing antibodies for three CVB serotypes: CVB1, CVB3, and CVB4. Using data from the national enterovirus surveillance system, we compared the annual exposure rates for each serotype in our cohort to infections reported across the United States. 98 pregnancies with no genetic defects were included. Overall, 29.6% (29/98) had positive IgG and 4.1% (4/98) of women had positive CVB IgM titers. To explore first-trimester CVB exposure, we focused exclusively on the 26 women with positive IgG and negative IgM titers. 61.5% (16/26) had neutralizing antibodies against a single serotype and 38.5% (10/26) against multiple CVB serotypes. CVB4 neutralizing antibodies were the most common (65.4%, 17/26), followed by CVB3 (53.9%, 14/26) and CVB1 (30.8%, 8/26). Among these, 30.8% of babies presented pulmonary valve anomalies: 19.2% (5/26) pulmonary atresia, and 11.5% (3/26) pulmonary stenosis. 23.1% (6/26) of babies had coronary sinusoids. CVB exposure in our cohort mirrored that of reported infections in the United States. Our results suggest a possible association between gestational CVB exposure and specific CHD, particularly pulmonary valve anomalies and coronary sinusoids. Supplementary Information The online version contains supplementary material available at 10.1007/s00246-021-02805-9.

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Section: Introductionmentioning

confidence: 99%

Possible Association of Pulmonary Atresia with In-Utero Coxsackievirus B Exposure

et al. 2022

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“…Further, although CAR is the main CVB receptor, different CVB serotypes rely on CAR to different extents. In general, CVB2, CVB4, and CVB6 use only CAR to mediate signal transduction; in contrast, CVB1, CVB3, and CVB5 bind to CAR and decay‐accelerating factor (DAF) (Hafenstein et al, 2007; Shafren et al, 1995; Sharma, Perry, & Eghtesady, 2021). Both CAR and DAF are known to be expressed in the heart suggesting different CVB serotypes can use different mechanisms to cause pathology (Lin et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…All CVB subtypes appear to use the common Coxsackie and Adenovirus Receptor (CAR) for cell entry; there are subtle differences; however, in tropism of the viruses which have been attributed to use of possible alternate receptors such as decay‐accelerating factor (DAF) (Hafenstein et al, 2007; Shafren et al, 1995; Sharma, Perry, & Eghtesady, 2021). Given our observations following prenatal infection of mice with CVB3 and to confirm the preceding associations between CVB1 and CVB4 infection and developmental issues, we investigated phenotypic differences in mouse fetuses exposed to alternate subtypes of CVB focusing on CVB1, CVB3, and CVB4 only.…”

Section: Introductionmentioning

confidence: 99%

Multiple subtypes of coxsackievirus group B can cause congenital heart disease

Sharma

Goessling

Brar

et al. 2022

Birth Defects Research

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Background: Different serotypes of coxsackievirus B (CVB), which is the most common cause of viral myocarditis, target cardiomyocytes through Coxsackie and Adenovirus Receptor and Decay-Accelerating Factor. Both receptors are expressed in the fetal heart. We hypothesized that infection with different serotypes of CVB during early pregnancy plays a role in pathogenesis of congenital heart defect (CHD).Methods: In this study, we use a murine model to infect with CVB1, CVB4, and combination of CVB3 + CVB4 during a critical period in gestation. We examined offspring of pregnant mice for fetal death and heart defects following viral infection. Result: Fetuses from uninfected control dams showed normal heart development, while maternal CVB infection precipitates CHD: majorly ventricular septal defects (VSD) and non-compaction of ventricular myocardium (NC), with some infrequent cases of double outlet right ventricle, left ventricle wall rupture, right ventricle hypertrophy, and thickened/dysplastic semilunar valves. Infection of pregnant dams with CVB1 leads to 44% VSD and 41.2% NC cases, while with CVB4 leads to 31.7% VSD and 13.3% NC cases. Co-infection with CVB3 + CVB4 increases fetal pathology to 51.3% VSD and 41% NC cases.Infection can also result in fetal death, with higher incidences with CVB3 + CVB4 with 46.2% cases, compared to 33.3% by CVB1 and 21.7% by CVB4. Male fetuses were more susceptible to all phenotypes. Conclusion:Our report shows that prenatal CVB infections can lead to pathogenesis of certain heart defects in mouse model, particularly exacerbated with co-infections. This data confirms a link between prenatal CVB infection and CHD development and highlights it is not unique to just one serotype of CVB.

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“…To perform in-depth studies of the role of CXADR in cardiac functions at different embryonic and adult stages, several conditional CXADR knockout mouse models have been generated ( Table 1 ). Research focusing on the role in cardiac development and pathogenesis using these conditional knockout models has been extensively reviewed [ 30 ], readers are encouraged to refer there.…”

Section: Cxadr Knockout and Overexpression Mouse Modelsmentioning

confidence: 99%

CXADR: From an Essential Structural Component to a Vital Signaling Mediator in Spermatogenesis

Zhang

Lui

2023

IJMS

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Canonical coxsackievirus and adenovirus receptor (CXADR) is a transmembrane component of cell junctions that is crucial for cardiac and testicular functions via its homophilic and heterophilic interaction. CXADR is expressed in both Sertoli cells and germ cells and is localized mainly at the interface between Sertoli-Sertoli cells and Sertoli-germ cells. Knockout of CXADR in mouse Sertoli cells specifically impairs male reproductive functions, including a compromised blood-testis barrier, apoptosis of germ cells, and premature loss of spermatids. Apart from serving as an important component for cell junctions, recent progress has showed the potential roles of CXADR as a signaling mediator in spermatogenesis. This review summarizes current research progress related to the regulation and role of CXADR in spermatogenesis as well as in pathological conditions. We hope this review provides some future directions and a blueprint to promote the further study on the roles of CXADR.

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Role of coxsackie‐adenovirus receptor in cardiac development and pathogenesis of congenital heart disease

Cited by 4 publications

References 67 publications

Possible Association of Pulmonary Atresia with In-Utero Coxsackievirus B Exposure

Possible Association of Pulmonary Atresia with In-Utero Coxsackievirus B Exposure

Multiple subtypes of coxsackievirus group B can cause congenital heart disease

CXADR: From an Essential Structural Component to a Vital Signaling Mediator in Spermatogenesis

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