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Alison M Kesson

Publications and source records attributed to Alison M Kesson.

9 recordsLinked to original sources

Immunopathology of flavivirus infections.

With the recent emergence of the flavivirus, West Nile virus (WNV), in particular, the New York strain of Lineage I WNV in North America in 1999, there has been a significant increase in activity in neurotropic flavivirus research. These viruses cause encephalitis that can result in permanent neurological sequelae or death. Attempts to develop vaccines have made progress, but have been variably successful, despite considerable commercial underwriting. Thus, the discovery of ways and means to combat disease is no less urgent. As such, most recent work has been directed towards dissecting and understanding the pathogenesis of disease, as a way of informing possible approaches to abrogation or amelioration of illness. Whether inherent to flaviviruses or because humans are incidental, dead-end hosts, it is clear that these viruses interact with their human hosts in extremely complex ways. This occurs from the cellular level, at which infection must be established to produce disease, to its interaction with the adaptive immune response, which may result in its eradication, with or without immunopathological and consequent neurological sequelae. As human proximity to and contact with flavivirus insect vectors and amplifying hosts cannot practically be eliminated, our understanding of the pathogenesis of flavivirus-induced diseases, especially with regard to possible targets for treatment, is imperative.

Animals↗

Clinical implications of mother-to-child transmission of HCV.

UNLABELLED: Testing for vertical transmission of hepatitis C virus (HCV) infection in infants and children will enable early identification of the majority of uninfected HCV-exposed infants and children, and will provide significant emotional relief for the parents. CONCLUSION: The small percentage of infected children should be offered enrollment in well-designed clinical trials of optimal medical management for prevention of the predicted long-term outcomes of chronic HCV infection: chronic hepatitis, cirrhosis and hepatocellular carcinoma.

Child↗

Salmonella typhimurium phage type 170 in a tertiary paediatric hospital with person-to-person transmission implicated.

Nosocomially-acquired salmonellosis is uncommonly reported in Australia. We report a cluster of gastroenteritis caused by Salmonella Typhimurium phage type 170 (STm 170) centred on a tertiary paediatric hospital in Sydney, New South Wales from 8 to 19 May 2004. A total of 12 children had STm 170 isolated from faecal specimens. Of the 12 cases, seven were acquired in hospital and five in the community. The mean age of the cases was 4.1 years (range: 2 months to 11.2 years). We conducted a case series investigation to generate hypotheses regarding the cause of this outbreak. Standardised interviews with cases' parents were conducted to identify potential exposures including in recently consumed food. An environmental investigation mapped the food preparation and storage areas, movements of staff caring for cases, relative case-bed locations, and duration of stay in these locations. Five of the seven hospital-acquired cases were immunocompromised with a history of prolonged and/or multiple hospital admissions. We found that STm 170 was probably brought into the hospital by a community-acquired case and spread to other in-patients through person-to-person transmission by hospital staff and/or patients. This study emphasises the importance of stringent compliance with hospital infection control practices at all times.

Child↗

The role of tumor necrosis factor in modulating responses of murine embryo fibroblasts by flavivirus, West Nile.

Murine embryo fibroblasts (MEF) transcribe tumor necrosis factor (TNF) mRNA and secrete soluble TNF in response to infection by West Nile virus (WNV) and TNF was demonstrated to be protective against WNV infection in vitro. TNF is not required for the WNV-induced upregulation of MHC-I expression on MEF, as TNF deficiency did not affect the upregulation of major histocompatibility complex class I (MHC-I) by WNV. Furthermore, NF-kappaB was activated by WNV in TNF-deficient MEF, demonstrating that WNV induces NF-kappaB activation in a TNF-independent manner. The subunits of NF-kappaB activated by TNF and WNV differed, WNV-activated a p65/p50 NF-kappaB complex while TNF-activated NF-kappaB was composed of p65, p50, and c-Rel. Furthermore, TNF-induced activation of NF-kappaB occurred earlier than WNV-induced NF-kappaB activation. The data demonstrate that WNV infection of MEF is associated with TNF production, but the WNV-induced activation of NF-kappaB and subsequent upregulation of MHC-I by WNV is TNF-independent.

Animals↗

Major histocompatibility complex class I (MHC-I) induction by West Nile virus: involvement of 2 signaling pathways in MHC-I up-regulation.

Type 1 interferon (IFN) receptor gene knockout (IFNAR(-/-)) mouse embryo fibroblasts (MEFs) are more susceptible to and productive of West Nile virus (WNV) and produce less type 1 IFN than WNV-infected wild-type (wt) MEFs. WNV infection of IFNAR(-/-) MEFs induced activation of a p65/p50 heterodimer of nuclear factor (NF)- kappa B and up-regulation of cell-surface expression of major histocompatibility complex class I (MHC-I) molecules. WNV infection of wt MEFs resulted in a greater up-regulation of MHC-I than did infection of IFNAR(-/-) MEFs because of the action of endogenous type 1 IFN production. IFN- beta -treatment of wt MEFs did not activate NF- kappa B but did up-regulate cell-surface MHC-I expression. The WNV-induced NF- kappa B activation was partially abrogated by the serine protease inhibitor N-benzoyl-l-tosyl-l-phenylalanine, which also abrogated the up-regulation of MHC-I. Thus, we demonstrate 2 pathways for WNV-induced up-regulation of MHC-I, a WNV-induced NF- kappa B-dependent, IFN-independent pathway and an NF- kappa B-independent, IFN-dependent pathway.

Animals↗

Influenza A associated morbidity and mortality in a Paediatric Intensive Care Unit.

This paper reports the clinical features and outcome of all children with a laboratory proven diagnosis of influenza A virus infection admitted to a major Paediatric Intensive Care Unit (PICU) in 2003. Eight of the 22 patients with influenza A virus infection (A/Fujian/411/2002-like type) presented with encephalopathy and three of the 22 patients died. This can be compared with 44 admissions and seven (16%) deaths of patients with influenza virus admitted in the same PICU in the preceding 15 years. In the present cohort, four (18%) of the 22 patients, including one child who died, should have received influenza vaccine according to the current Australian immunisation recommendations. We have no documented evidence that any of the 22 children received influenza vaccination. During the 2003 influenza season there was an increased number of children admitted to our PICU with influenza A infection and an increased number of deaths compared with previous years. Influenza infection causes significant morbidity and mortality in young children, most of whom are not currently recommended for annual influenza vaccination.

Adolescent↗

Immune modulation by flaviviruses.

Flaviviruses cause pleomorphic disease with significant morbidity and mortality worldwide. Interestingly, in contrast to most viruses, which subvert or avoid host immune systems, members of the neurotropic Japanese encephalitis serocomplex cause functional changes associated with increased efficacy of the immune response. These viruses induce increased cell surface expression of immune recognition molecules, including class I and II major histocompatibility complex (MHC) and various adhesion molecules. Increases are functional: infected cells are significantly more susceptible to both virus- and MHC-specific cytotoxic T cell lysis. Induced changes are modulated positively or negatively by Th1 and Th2 cytokines, as well as by cell cycle position and adherence status at infection. Infection also increases costimulatory molecule expression on Langerhans cells in the skin. Local interleukin-1 beta production causes accelerated migration of phenotypically altered Langerhans cells to local draining lymph nodes, where initiation of antiviral immune responses occur. The exact mechanism(s) of upregulation is unclear, but changes are associated with NF-kappa B activation and increased MHC and ICAM-1 gene transcription, independently of interferon (IFN) or other proinflammatory cytokines. Increased MHC and adhesion molecule expression may contribute to the pathogenesis of flavivirus encephalitis. Results from a murine model of flavivirus encephalitis developed in this laboratory suggest that fatal disease is immunopathological in nature, with IFN-gamma playing a crucial role. We hypothesize that these viruses may decoy the adaptive immune system into generating low-affinity T cells, which clear virus poorly, as part of their survival strategy. This may enable viral growth and immune escape in cycling cells, which do not significantly upregulate cell surface molecules.

Animals↗

Interaction of flaviviruses with cells of the vertebrate host and decoy of the immune response.

Flaviviruses cause endemic and epidemic disease with significant morbidity and mortality throughout the world. In contrast to viruses that avoid the host immune response by down-regulating cell surface major histocompatibility complex expression, infection by members of the neurotropic Japanese encephalitis serogroup induce virus-directed functional increases in expression of class I and II major histocompatibility complex and various adhesion molecules, resulting in increased susceptibility to both virus- and major histocompatibility complex-specific cytotoxic T lymphocyte lysis. These changes are comodulated by T1 and T2 cytokines, as well as by cell cycle position and adherence status at infection. Infected skin dendritic (Langerhans) cells also show increased costimulatory molecule expression and local interleukin-1beta production causes accelerated migration of Langerhans cells to local draining lymph nodes, where initiation of antiviral immune responses occur. The exact mechanism(s) of up-regulation is unclear, but changes are associated with NF-kappaB activation and increased MHC and ICAM-1 gene transcription, independently of interferon or other pro-inflammatory cytokines. We hypothesize that these viruses may decoy the adaptive immune system into generating low-affinity, self-reactive T cells which clear virus poorly, as part of their survival strategy. This may enable viral growth and immune escape in cycling cells, which do not significantly up-regulate cell surface molecules. A possible side-effect of this might be immunopathology, caused by 'autoimmune' cross-reactive damage of uninfected high major histocompatibility complex and adhesion molecule-expressing cells, with consequent exacerbation of encephalitic disease. Results from a murine model of flavivirus encephalitis developed in this laboratory further suggest that interferon-gamma plays a crucial role in fatal immunopathology.

Animals↗

Regulation of immune recognition molecules by flavivirus, West Nile.

We have shown the flaviviruses can up-regulate the cell surface expression of the immune recognition molecules, major histocompatability complex class-I and class-II (MHC-I, MHC-II), ICAM-1, VCAM, and E-selectin, in an interferon-independent and tumor necrosis factor-independent manner. This up-regulation is associated with an increased transcription of the relevant genes and is due to activation of the transcription factor, nuclear factor-kappa B. The level of up-regulation is determined in part by the cell cycle position of the cell when infected with the flavivirus, as quiescent cells show a greater increase in the level of expression of the immune recognition molecules, MHC-I and ICAM-1, than cells in other phases of the cell cycle. The resultant increased cell surface expression is functional with the increased expression resulting in increased recognition by flavivirus-specific and allo-specific cytotoxic T cells.

Animals↗