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Biomedical subjects

A S Lalani

Publications and source records attributed to A S Lalani.

11 recordsLinked to original sources
PubMed2000

Modulating chemokines: more lessons from viruses.

Chemokines are crucial effector molecules involved in orchestrating the host inflammatory response against invading pathogens. Viruses have devised several strategies for exploiting or neutralizing chemokines or their receptors to further their own propagation or elude host defenses. Insight into strategies used by viruses to modulate chemokines might help generate novel approaches for treating viral diseases and chemokine-mediated inflammatory disorders.

Animals↗
PubMed1999

Use of chemokine receptors by poxviruses.

Chemokine receptors serve as portals of entry for certain intracellular pathogens, most notably human immunodeficiency virus (HIV). Myxoma virus is a member of the poxvirus family that induces a lethal systemic disease in rabbits, but no poxvirus receptor has ever been defined. Rodent fibroblasts (3T3) that cannot be infected with myxoma virus could be made fully permissive for myxoma virus infection by expression of any one of several human chemokine receptors, including CCR1, CCR5, and CXCR4. Conversely, infection of 3T3-CCR5 cells can be inhibited by RANTES, anti-CCR5 polyclonal antibody, or herbimycin A but not by monoclonal antibodies that block HIV-1 infection or by pertussis toxin. These findings suggest that poxviruses, like HIV, are able to use chemokine receptors to infect specific cell subtypes, notably migratory leukocytes, but that their mechanisms of receptor interactions are distinct.

3T3 Cells↗
PubMed1999

Role of the myxoma virus soluble CC-chemokine inhibitor glycoprotein, M-T1, during myxoma virus pathogenesis.

Myxoma virus is a poxvirus that causes a virulent systemic disease called myxomatosis in European rabbits. Like many poxviruses, myxoma virus encodes a variety of secreted proteins that subvert the antiviral activities of host cytokines. It was recently demonstrated that the myxoma virus M-T1 glycoprotein is a member of a large poxvirus family of secreted proteins that bind CC-chemokines and inhibit their chemoattractant activities in vitro. To determine the biological role of M-T1 in contributing to myxoma virus virulence, we constructed a recombinant M-T1-deletion mutant virus that was defective in M-T1 expression. Here, we demonstrate that M-T1 is expressed continuously during the course of myxoma virus infection as a highly stable 43-kDa glycoprotein and is dispensable for virus replication in vitro. Deletion of M-T1 had no significant effects on disease progression or in the overall mortality rate of infected European rabbits but heightened the localized cellular inflammation in primary tissue sites during the initial 2 to 3 days of infection. In the absence of M-T1 expression, deep dermal tissues surrounding the primary site of virus inoculation showed a dramatic increase in infiltrating leukocytes, particularly monocytes/macrophages, but these phagocytes remained relatively ineffective at clearing virus infection, likely due to the concerted properties of other secreted myxoma virus proteins. We conclude that M-T1 inhibits the chemotactic signals required for the influx of monocytes/macrophages during the acute-phase response of myxoma virus infection in vivo, as predicted by its ability to bind and inhibit CC-chemokines in vitro.

Animals↗
PubMed1999

Immunomodulation by viruses: the myxoma virus story.

Myxoma virus is a poxvirus pathogen of rabbits that has evolved to replicate successfully in the presence of an active immune response by an infected host. To accomplish this, the virus has developed a variety of strategies to avoid detection by or obstruct specific aspects of the antiviral response whose consolidated action is antagonistic to virus survival. We describe two distinct viral strategies carried out by viral proteins with which myxoma virus subverts the host immune response. The first strategy is the production of virus-encoded proteins known as viroceptors or virokines that mimic host receptors or cytokines. These seek to actively block extracellular immune signals required for effective virus clearance and produce a local environment in the infected tissue that is "virus friendly". The second strategy, carried out by intracellular viral proteins, seeks to retard the innate antiviral responses such as apoptosis, and hinder attempts by the infected cell to communicate with the cellular arm of the immune system. By studying these viral strategies of immune evasion, the myxoma system can provide insights into virus-host interactions and also provide new insights into the complex immune system.

Amino Acid Sequence↗
PubMed1998

Functional comparisons among members of the poxvirus T1/35kDa family of soluble CC-chemokine inhibitor glycoproteins.

Many poxviruses express a 35-40-kDa secreted protein, termed "T1" (for leporipoxviruses) or "35kDa" (for orthopoxviruses), that binds CC-chemokines with high affinity but is unrelated to any known cellular proteins. Many previously identified poxvirus cytokine-binding proteins display strict species ligand-binding specificity. Because the T1 and 35kDa proteins share only 40% amino acid identity, we compared the abilities of purified myxoma virus-T1 (M-T1) and vaccinia virus (strain Lister)- and rabbitpox virus-35kDa proteins to inhibit human CC-chemokines in vitro. All three proteins were equally effective in preventing several human CC-chemokines from binding to target chemokine receptors and blocking subsequent intracellular calcium release. The inhibitory affinities were comparable (Ki = 0.07-1.02 nM). These proteins also displayed similar abilities to inhibit (IC50 = 6.3-10.5 nM) human macrophage inflammatory protein-1alpha-mediated chemotaxis of human monocytes. None of the viral proteins blocked interleukin-8-mediated calcium flux or chemotaxis of human neutrophils, confirming that the biological specificity of the T1/35kDa family is targeted inhibition of CC-chemokines. Despite the significant sequence divergence between the leporipoxvirus T1 and orthopoxvirus 35kDa proteins, our data suggest that their CC-chemokine binding and inhibitory properties appear to be species nonspecific and that the critical motifs most likely reside within the limited regions of conservation.

Calcium↗
PubMed1997

The T1/35kDa family of poxvirus-secreted proteins bind chemokines and modulate leukocyte influx into virus-infected tissues.

Immunomodulatory proteins encoded by the larger DNA viruses interact with a wide spectrum of immune effector molecules that regulate the antiviral response in the infected host. Here we show that certain poxviruses, including myxoma virus. Shope fibroma virus, rabbitpox virus, vaccinia virus (strain Lister), cowpox virus, and raccoonpox virus, express a new family of secreted proteins which interact with members of both the CC and CXC superfamilies of chemokines. However, swinepox virus and vaccinia virus (strain WR) do not express this activity Using a recombinant poxviruses, the myxoma M-T1 and rabbitpox virus 35kDa secreted proteins were identified as prototypic members of this family of chemokine binding proteins. Members of this T1/35kDa family of poxvirus-secreted proteins share multiple stretches of identical sequence motifs, including eight conserved cysteine residues, but are otherwise unrelated to any cellular genes in the database. The affinity of the CC chemokine RANTES interaction with M-T1 was assessed by Scatchard analysis and yielded a Kd of approximately 73 nM. In rabbits infected with a mutant rabbitpox virus, in which the 35kDa gene is deleted, there was an increased number of extravasating leukocytes in the deep dermis during the early phases of infection. These observations suggest that members of the T1/35kDa class of secreted viral proteins bind multiple members of the chemokine superfamily in vitro and modulate the influx of inflammatory cells into virus-infected tissues in vivo.

Amino Acid Sequence↗
PubMed1997

Secreted poxvirus chemokine binding proteins.

Poxviruses encode a variety of immunomodulatory proteins that subvert the cytokine networks of infected hosts. Myxoma virus, a poxvirus pathogen of rabbits, expresses two distinct 35- to 40-kDa secreted glycoproteins that bind a broad spectrum of chemokines. The first of these, designated M-T7, is encoded by the T7 gene and is the first example of what is here referred to as type-I chemokine binding protein (CBP-I). M-T7 was initially discovered as a secreted viral homologue of cellular interferon-gamma receptor but binding studies indicate that purified M-T7 protein also interacts with members of the CXC, CC, and C chemokine families through the conserved heparin-binding domains. The second myxoma protein, M-T1, also called CBP-II, is a member of a larger superfamily of poxvirus proteins that includes related secreted 35-kDa proteins encoded by a wide variety of orthopoxviruses. Deletion analysis of either CBP-I or -II genes within recombinant poxvirus constructs revealed profound alterations in the trafficking of infiltrating leukocytes into virus-infected lesions. It is proposed that the interaction of CBP-I with the conserved heparin-binding domains found on most chemokines represents a novel mechanism for altering multiple chemokine functions in vivo. In summary, CBP-I and CBP-II are the first examples of secreted virus proteins that bind to multiple chemokine family members as part of a strategy to prevent the early phase of inflammatory cell migration into virus-infected tissues.

Animals↗
PubMed1997

The purified myxoma virus gamma interferon receptor homolog M-T7 interacts with the heparin-binding domains of chemokines.

The myxoma virus T7 protein M-T7 is a functional soluble gamma interferon receptor homolog that has previously been shown to bind gamma interferon and inhibit its antiviral activities in a species-specific manner, but gene knockout analysis has suggested a further role for M-T7 in blocking leukocyte influx into infected lesions. We purified M-T7 to apparent homogeneity and showed that M-T7 is an N-linked glycoprotein that appears to be a stable homotrimer with a molecular mass of approximately 113 kDa in solution. M-T7, in addition to forming inhibitory complexes with rabbit gamma interferon, was also shown to bind to human interleukin-8, a prototypic member of the chemokine superfamily. Moreover, M-T7 was able to interact promiscuously with all members of the CXC, CC, and C chemokine subfamilies tested. Binding of human RANTES to M-T7 can be competed by rabbit gamma interferon and also by cold RANTES competitor with a 50% inhibitory concentration of 900 nM. Although M-T7 retains binding to a number of interleukin-8 N-terminal (ELR) deletion mutants, binding to mutants containing deletions in the C-terminal heparin-binding domain of interleukin-8 is abrogated. Furthermore, heparin effectively competes the interaction of M-T7 with the chemokine RANTES but not with rabbit gamma interferon. We propose that this novel M-T7 interaction with members of the chemokine superfamily may be facilitated through the conserved heparin-binding domains found in a wide spectrum of chemokines and that M-T7 may function by modulating chemokine-glycosaminoglycan interactions in virus-infected tissues.

Animals↗
PubMedDate not supplied

Evasion and exploitation of chemokines by viruses.

Chemokines and chemokine receptors play a critical role in the host defense against viruses by mobilizing leukocytes to sites of infection, injury and inflammation. In order to replicate successfully within their host organisms, viruses have devised novel strategies for exploiting or subverting chemokine networks. This review summarizes various mechanisms that are currently known to be used by viruses for modulating chemokine activities including viral homologs of chemokines and chemokine receptors and soluble viral chemokine binding proteins. Insight into these strategies is providing a wealth of information on viral-host interactions, the function of chemokines in host defense and may help to generate novel anti-chemokine agents for treating against viral diseases or inflammatory disorders.

Animals↗
PubMedDate not supplied

Sensorineural impairment in unilateral otosclerosis.

Audiometric findings were evaluated in a group of patients with clinical unilateral otosclerosis. A comparison was made between bone conduction threshold in the better hearing ear and the ear with the mixed hearing loss. Over 50% of the patients had a significant elevation in the bone conduction thresholds in the ear with clinical otosclerosis as compared to the uninvolved ear. A pair of temporal bones from a patient with unilateral otosclerosis and unilateral mixed hearing loss is presented.

Adult↗