Animal morbilliviruses and their cross-species transmission potential.

Like measles virus (MV), whose primary hosts are humans, non-human animal morbilliviruses use SLAM (signaling lymphocytic activation molecule) and PVRL4 (nectin-4) expressed on immune and epithelial cells, respectively, as receptors. PVRL4's amino acid sequence is highly conserved across species, while that of SLAM varies significantly. However, non-host animal SLAMs often function as receptors for different morbilliviruses. Uniquely, human SLAM is somewhat specific for MV, but canine distemper virus, which shows the widest host range among morbilliviruses, readily gains the ability to use human SLAM. The host range for morbilliviruses is also modulated by their ability to counteract the host's innate immunity, but the risk of cross-species transmission of non-human animal morbilliviruses to humans could occur if MV is successfully eradicated.

Comparative sequence analysis of morbillivirus receptors and its implication in host range expansion.

SLAM (CD150) and nectin-4 are the major morbillivirus receptors responsible for virus pathogenesis and host range expansion. Recently, morbillivirus infections have been reported in unnatural hosts, including endangered species, posing a threat to their conservation. To understand the host range expansion of morbilliviruses, we generated the full-length sequences of morbillivirus receptors (goat, sheep, and dog SLAM, and goat nectin-4) and tried to correlate their role in determining host tropism. A high level of amino acid identity was observed between the sequences of related species, and phylogenetic reconstruction showed that the receptor sequences of carnivores, marine mammals, and small ruminants grouped separately. Analysis of the ligand binding region (V region; amino acid residues 52-136) of SLAM revealed high amino acid identity between small ruminants and bovine SLAMs. Comparison of canine SLAM with ruminants and non-canids SLAM revealed appreciable changes, including charge alterations. Significant differences between feline SLAM and canine SLAM have been reported. The binding motifs of nectin-4 genes (FPAG motif and amino acid residues 60, 62, and 63) were found to be conserved in sheep, goat, and dog. The differences reported in the binding region may be responsible for the level of susceptibility or resistance of a species to a particular morbillivirus.

The tumor-associated marker, PVRL4 (nectin-4), is the epithelial receptor for morbilliviruses.

PVRL4 (nectin-4) was recently identified as the epithelial receptor for members of the Morbillivirus genus, including measles virus, canine distemper virus and peste des petits ruminants virus. Here, we describe the role of PVRL4 in morbillivirus pathogenesis and its promising use in cancer therapies. This discovery establishes a new paradigm for the spread of virus from lymphocytes to airway epithelial cells and its subsequent release into the environment. Measles virus vaccine strains have emerged as a promising oncolytic platform for cancer therapy in the last ten years. Given that PVRL4 is a well-known tumor-associated marker for several adenocarcinoma (lung, breast and ovary), the measles virus could potentially be used to specifically target, infect and destroy cancers expressing PVRL4.

Specific alteration of the expression of selected hypothalamic neuropeptides during acute and late mouse brain infection using a morbillivirus: relevance to the late-onset obesity?

Neurotropic viruses are involved in pathologies of the central nervous system, triggering transient or irreversible disorders, such as neurological diseases or homeostasis imbalance. In experimental animals, viruses have been shown to cause obesity, a complex disease depending on multiple factors, including genetic susceptibility and environmental components. Using a mouse model of virally induced obesity following brain infection by the Canine Distemper Virus (CDV), a morbillivirus closely related to the human measles virus, we investigated the modulation of expression of several hypothalamic neuropeptides known to intervene in the regulation of body weight and energy expenditure, both during the acute and late stages of infection. During the acute stage, while viral replication occurs, we found a dramatic decrease of expressions of neuropeptides, in particular neuropeptide Y, melanin-concentrating hormone (MCH), hypocretin, vasopressin and tachykinins, the magnitude of which seemed to be linked to the viral burden and the individual susceptibility. The effect of the virus, however, varied with the hypothalamic nucleus and neuropeptide involved, suggesting that certain circuits were affected while others remained intact. During the late stage of infection, marked recovery to the initial hypothalamic levels of peptide expression was seen in a number of lean animals, suggesting recovery of homeostasis equilibrium. Interestingly, some neuropeptidergic systems remained disturbed in mice exhibiting obese phenotype, arguing for their involvement in triggering/maintaining obesity. Even though our data could not fully explain the viral-induced obesity, they may be helpful in understanding the molecular events associated with obesity and in investigating therapeutic alternatives.

Bioaccumulation of polychlorinated biphenyls (PCBs) and dichlorodiphenylethane (DDE) methyl sulfones in tissues of seal and dolphin morbillivirus epizootic victims.

Polychlorinated biphenyl (PCB) and dichlorodiphenylethane (DDE) methyl sulfone (MSF) metabolites possess high affinities for binding two homologous 16,000 Da homodimeric receptor proteins in the lung (Clara cell secretory protein, CCSP) and the uterus (uteroglobin, UG), leading to selective bioaccumulation of MSFs in these tissues. As marine mammals are highly exposed to organochlorines, concentrations of PCBs, PCB MSFs, DDT, and DDE MSF were analyzed in blubber, lung, and uterus samples from harbor seal (Phoca vitulina) and striped dolphin (Stenella coeruleoalba) morbillivirus epizootic victims to investigate uterine and lung MSF accumulation. Mean uterus concentrations of PCB MSFs and DDE MSF in harbor seals were 0.61 and 0.04 microg/g lipid weight and in striped dolphins 0.05 and 0.01 microg/g lipid weight. Mean lung concentrations of PCB MSFs and DDE MSF in harbor seals were 0.96 and 0.02 microg/g lipid weight and in striped dolphins 0.16 and 0.01 microg/g lipid weight. To ascertain whether uterine and lung bioaccumulation of MSFs is possible due to the presence of CCSP and UG in seals, CCSP and UG proteins in uterine flushings and in uterine and lung and epithelial tissue from Baltic gray and ringed seals were characterized using gel electrophoresis and Western blotting techniques. UG- and CCSP-like proteins with molecular weights of 16,000 Da were resolved in all samples. This is the first demonstration of this protein in any marine mammalian species. The toxicological implications of MSF binding with UG and CCSP in marine mammals are discussed.

Abnormally high polychlorinated biphenyl levels in striped dolphins (Stenella coeruleoalba) affected by the 1990-1992 Mediterranean epizootic.

PCB concentrations and total lipid content were determined in the blubber and liver of striped dolphins affected by the 1990 morbillivirus epizootic in the Mediterranean Sea, and in the blubber of striped dolphins from the same area sampled with a biopsy dart in 1987-1989 and 1991. PCB levels were found to be significantly higher in the individuals that succumbed to the epizootic than in the 'healthy' population sampled before or after the event. Although recent mobilization of lipid reserves was found to have occurred in some of the diseased dolphins, this had little effect on their PCB blubber concentrations and cannot explain the observed difference with the healthy individuals. Three hypotheses are put forward to explain the apparent link between high PCB levels and mortality caused by the epizootic: (i) depressed immunocompetence caused by PCBs leading to an increase in individual susceptibility to the morbillivirus infection, (ii) mobilization of fat reserves leading to increased PCB levels in blood which, in turn, may produce a liver lesion capable of increasing the individual's susceptibility to the morbillivirus infection, and (iii) previous existence of an unspecific hepatic lesion producing impairment of the liver function which, in turn, could lead to an increase both in tissue PCB concentrations and in individual susceptibility to the morbillivirus infection.