Human cytomegalovirus as a direct pathogen: Correlation of multiorgan involvement and cell distribution with clinical and pathological findings in a case of congenital inclusion disease

Abstract

The human cytomegalovirus (HCMV), a member of the Herpesviridae, is the most frequent cause of congenital virus infections and a major cause of morbidity and mortality in immunocompromised patients. Due to the lack of an appropriate animal model, insight into the pathogenesis of HCMV infections originates primarily from in situ examination of HCMV-infected tissues. Although in immunocompromised adults such tests are complicated frequently by the presence of additional misleading pathogens, the absence of additional pathogens renders congenital inclusion disease the most suitable access for investigation of pathogenetic aspects of HCMV infections. Immunohistochemical examination of tissue sections from a boy with fatal congenital inclusion disease was undertaken to detect the extent of multiorgan and cell involvement. Adrenal gland, bone marrow, diencephalon, heart, kidney, liver, lung, pancreas, placenta, small bowel and spleen were included in this study. Detection of virus antigens from different phases of viral replication revealed that all investigated organs were infected by HCMV. Simultaneous detection of cell type specific marker molecules showed that a variety of cell types stained positive for HCMV antigens including endothelial cells, epithelial cells, smooth muscle cells, mesenchymal cells, hepatocytes, monocytes/macrophages and granulocytes. The lung, the pancreas, the kidneys and the liver were the major target organs with a high number of HCMV infected cells. This correlated with multiorgan failure as the cause of death and strongly indicates direct pathogenetic effects of HCMV.

Reconstruction of the complete human cytomegalovirus genome in a BAC reveals RL13 to be a potent inhibitor of replication

“…HCMV is also the leading viral cause of congenital disability and malformation, which was the primary basis for it being designated a highest priority level vaccine target by the US Institute of Medicine (2). HCMV disease can manifest as a wide range of clinical conditions (e.g., pneumonia, colitis, retinitis, hepatitis, arteriosclerosis, or systemic infection), reflecting the capacity of the virus to infect a wide range of cell types in vivo (3)(4)(5)(6)(7). Despite this wide tropism in vivo, only fibroblasts support the efficient growth of cultured strains in vitro.…”

Gene Functional Studies Using Bacterial Artificial Chromosome (BACs)

“…During acute infection of CMV in immune-compromised patients, a number of cell types, such as ECs, various leukocytes, epithelial cells, hepatocytes, smooth muscle cells, and fibroblasts, can be infected because of uncontrolled replication of viruses (Howell, Miller et al 1979;Myerson, Hackman et al 1984;Gnann, Ahlmen et al 1988;Wiley and Nelson 1988;Dankner, McCutchan et al 1990;Sinzger, Grefte et al 1995;Read, Zhang et al 1999;Bissinger, Sinzger et al 2002). ECs appear to play a critical role in the process of HCMV persistent active infection and maintenance within the host, which is controlled by genetic determinants.…”

Impaired Surfactant Production by Alveolar Epithelial Cells in a SCID-hu Lung Mouse Model of Congenital Human Cytomegalovirus Infection

“…In congenital infection, HCMV spreads extremely efficiently into fetal organs following fetal viremia. Although pneumonitis is rarely the sole manifestation of congenital HCMV disease in the neonate (62), histological examinations of HCMV-infected fetuses identified the lung as a major target organ, with a large number of HCMV-infected cells (8,25). The main burden of lung-associated HCMV diseases occurs during postnatal infection in premature infants (3,22,34,65) and in immunocompromised children (predominantly after organ or bone marrow transplantation) (27,30,67).…”

“…During congenital infection, the fetal lungs are particularly targeted by HCMV (8,25), and reductions in the levels of secretion of pulmonary surfactant, a complex substance that decreases surface tension, thus preventing alveolar collapse, into the amniotic fluid suggest that the virus negatively affects fetal lung maturation (50).…”