Intestinal HAdV Infection: Tissue Specificity, Persistence, and Implications for Antiviral Therapy

Abstract

Human adenovirus (HAdV) causes infections predominantly in early childhood and the tissue tropism of specific HAdV species determines the clinical manifestation, including infections of the gastrointestinal tract, respiratory tract, and keratoconjunctivitis. Why HAdV shows such a tropism has not yet been fully elucidated, but in the intestine different mechanisms for virus entry or resistence to immune modulatory factors have been described. Recently identified antiviral strategies by interferons provide evidence about the repression of E1A and maybe even promote HAdV persistence. The presence of HAdV in a persistent status in the gut is of importance in the setting of pediatric stem cell transplant recipients where HAdV detection in stool usually preceds clinical signs and severe infections are related to mortality. The reactivation of persistent intestinal HAdV infections in these patients needs further investigation also with regard to successful therapy options. In addition, several newly identified recombinant HAdV types have been isolated from stool samples, thus raising the question of possible recombination events in the gut. In this review, intestinal HAdV infections are discussed in relation to the tissue tropism, persistence, recombination, and new in-vitro models to enhance the knowledge about virus–host interactions and support the development of new treatment approaches.

<p>Epidemiology of Human Adenoviruses: A 20-Year Retrospective Observational Study in Hospitalized Patients in Bern, Switzerland</p>

“…39 In addition, it is known that specific HAdV species have distinct tissue tropism which may determine the clinical presentation. 40 The presence of HAdV in respiratory tract and stool samples from patients not presenting with any clinical symptoms might be detected incidentally, thus making interpretation of the clinical significance of a positive result difficult. Yet, in our study, samples of the patients who had any clinical presentation associated with HAdV infection were referred for laboratory diagnostics testing to our institute upon the request of the seeing physician when an adenovirus infection was suspected.…”

<p>Management of Adenoviral Keratoconjunctivitis: Challenges and Solutions</p>

“…See Table 1 for the subtypes of Group B and D HAdV. 11,12 HAdV type 3, 7, and 21 of Group B can cause keratoconjunctivitis, urinary tract infection, respiratory infection, and GIT infection. Group D HAdV can also cause both ocular and GIT infection.…”

“…17 Additionally, asymptomatic passage of adenovirus in the stool of patients with previous adenoviral GIT infection can also occur. 3,11 Kosulin et al suggested that latent HAdV infection of the gut lymphoid cell could serve as a source of release of HAdV particles in the community. 18 Garnett et al demonstrated the asymptomatic persistence of group C adenovirus in human mucosal T lymphocytes or lymphoid tissue following primary adenoviral infection.…”

“…17 The stimulation of these adenovirus containing mucosal T-lymphocytes results in reactivation of latent HAdV with consequential leakage of reactivated viruses into intestinal epithelial cells, where adenoviruses undergo replication and subsequent shedding in stool. 11,17,[19][20][21] This is indicative of persistent subclinical HAdV infection of the gut-associated lymphoid tissue. 20 Immunocompetent individuals are likely to shed less HAdV into their stool, in contrast to those who are immunocompromised, where significant amounts of HAdV are released.…”

Epigenetics and the dynamics of chromatin during adenovirus infections

“…Although rarely detected in peripheral blood lymphocytes [150][151][152], adenovirus is frequently found in lymphocytes residing in lymphoid organs of the oropharynx [153][154][155] and intestine [156][157][158]. Adenovirus may persist as a smoldering infection in the intestine from which it can be shed in the feces of asymptomatic individuals [150,159].…”