In Drosophila the equalization of X‐linked gene products between males and females, i.e. dosage compensation, is the result of a 2‐fold hypertranscription of most of these genes in males. At least four regulatory genes are required for this process. Three of these genes, maleless (mle), male‐specific lethal 1 (msl‐1) and male‐specific lethal 3 (msl‐3), have been cloned and their products have been shown to interact and to bind to numerous sites on the X chromosome of males, but not of females. Although binding to the X chromosome is negatively correlated with the function of the master regulatory gene Sex lethal (Sxl), the mechanisms that restrict this binding to males and to the X chromosome are not yet understood. We have cloned the last of the known autosomal genes involved in dosage compensation, male‐specific lethal 2 (msl‐2), and characterized its product. The encoded protein (MSL‐2) consists of 769 amino acid residues and has a RING finger (C3HC4 zinc finger) and a metallothionein‐like domain with eight conserved and two non‐conserved cysteines. In addition, it contains a positively and a negatively charged amino acid residue cluster and a coiled coil domain that may be involved in protein‐protein interactions. Males produce a msl‐2 transcript that is shorter than in females, due to differential splicing of an intron of 132 bases in the untranslated leader. Using an antiserum against MSL‐2 we have shown that the protein is expressed at a detectable level only in males, where it is physically associated with the X chromosome. Our observations suggest that MSL‐2 may be the target of the master regulatory gene Sxl and provide the basic elements of a working hypothesis on the function of MSL‐2 in mediating the 2‐fold increase in transcription that is characteristic of dosage compensation.

Trypomastigotes ofFor the first time it was possible to assign a defined ligand to a sequenced glycoprotein belonging to the gp85 family. This fact, together with the reported binding of family members to cell surfaces, reinforces the hypothesis that this family encodes glycoproteins with similar sequences but differing enough as to bind to different ligands and thus forming a family of adhesion glycoproteins enabling the parasite to overcome the barriers interposed by cell membranes, extracellular matrices, and basal laminae.

Intracerebral infection of mice with mouse hepatitis virus, a member of the Coronaviridae family, reproducibly results in an acute encephalomyelitis that progresses to a chronic demyelinating disease. The ensuing neuropathology during the chronic stage of disease is primarily immune mediated and similar to that of the human demyelinating disease multiple sclerosis. Secretion of chemokines within the CNS signals the infiltration of leukocytes, which results in destruction of white matter and neurological impairment. The CC chemokine ligand (CCL)5 is localized in white matter tracts undergoing demyelination, suggesting that this chemokine participates in the pathogenesis of disease by attracting inflammatory cells into the CNS. In this study, we administer a mAb directed against CCL5 to mice with established mouse hepatitis virus-induced demyelination and impaired motor skills. Anti-CCL5 treatment decreased T cell accumulation within the CNS based, in part, on viral Ag specificity, indicating the ability to differentially target select populations of T cells. In addition, administration of anti-CCL5 improved neurological function and significantly (p ≤ 0.005) reduced the severity of demyelination and macrophage accumulation within the CNS. These results demonstrate that the severity of CNS disease can be reduced through the use of a neutralizing mAb directed against CCL5 in a viral model of demyelination.

The CXC chemokine ligand 10 (CXCL10) is a non-ELR CXC chemokine that exerts a potent chemotactic effect on activated T cells through binding the receptor CXCR3 (5). CXCL10 is expressed within tissues following viral infection, suggesting an important role for this chemokine in host defense by contributing to lymphocyte activation, extravasation, and accumulation of virus-specific T cells within sites of infection. Indeed, recent studies with antibody-mediated targeting of CXCL10 and CXCL10 Ϫ/Ϫ mice demonstrated that the absence of CXCL10 function results in increased mortality accompanied by increased viral titers and reduced T-cell infiltration within the brains of mice infected intracerebrally with a murine coronavirus (mouse hepatitis virus [MHV]) (8,20). In addition, CXCL10 expression modulates the pathogenesis of liver disease in adenovirus-infected mice and transgenic mice capable of replicating hepatitis B virus by attracting CD8 ϩ T lymphocytes into the liver (2, 11).These studies indicate that CXCL10 functions as a sentinel molecule in host defense and is important in the development of a protective T-cell response following viral infection. Recent findings have also illustrated an important role for chemokines in innate defense following viral infection. For example, in addition to its chemotactic effect on T cells, CXCL10 has also been shown to induce natural killer (NK) cell migration following viral infection (2, 11, 22, 23). Expression of both CXCL10 and CXC chemokine ligand 9 (CXCL9) has been found to contribute to antiviral immune responses in the absence of T and B cells (24). Although these chemokines have a demonstrated direct antimicrobial effect (6), their protective effect following vaccinia virus infection was a result of enhanced NK cell trafficking and activation (24).Our laboratory is interested in the functional contributions of chemokines and chemokine receptors in both host defense and disease progression within the context of coronavirus infection of the central nervous system (CNS). Intracerebral infection of susceptible strains of mice with MHV results in an acute encephalomyelitis followed by a chronic immune-mediated demyelinating disease that is similar in pathology to the human demyelinating disease multiple sclerosis (16). A robust expression of chemokine genes occurs within the CNS following MHV infection that precedes and accompanies leukocyte entry (18).Although NK cells can be readily detected within the CNS early following MHV infection, their precise contributions to antiviral immune responses within the CNS have not been well established. Furthermore, CXCL10 is prominently expressed as early as day 1 postinfection, suggesting that this molecule may function in enhancing innate immune responses by attracting NK cells into the CNS. Therefore, to further understand the relationship between CXCL10 and the innate immune response to viral infection of the CNS, we constructed a recombinant MHV capable of expressing mouse CXCL10. Intracerebral infection of RAG1 Ϫ/Ϫ mice with t...