Inhibition of herpes simplex virus infection by lactoferrin is dependent on interference with the virus binding to glycosaminoglycans

Previous reports have indicated that lactoferrin inhibits herpes simplex virus (HSV) infection during the very early phases of the viral replicative cycle. In the present work we investigated the mechanism of the antiviral activity of lactoferrin in mutant glycosaminoglycan (GAG)-deficient cells. Bovine lactoferrin (BLf) was a strong inhibitor of HSV-1 infection in cells expressing either heparan sulfate (HS) or chondroitin sulfate (CS) or both, but was ineffective or less efficient in GAG-deficient cells or in cells treated with GAG-degrading enzymes. In contrast to wild-type HSV-1, virus mutants devoid of glycoprotein C (gC) were significantly less inhibited by lactoferrin in GAG-expressing cells, indicating that lactoferrin interfered with the binding of viral gC to cell surface HS and/or CS. Finally, we demonstrated that lactoferrin bound directly to both HS and CS isolated from surfaces of the studied cells, as well as to commercial preparations of GAG chains. The results support the hypothesis that the inhibition of HSV-1 infectivity by lactoferrin is dependent on its interaction with cell surface GAG chains of HS and CS.     

Modelling the transmission dynamics of Ross River virus in Southwestern Australia

During the 1995–1996 Australian financial year, over 1300notifications of Ross River (RR) virus disease were notifiedin humans from Southwestern Australia. Due to the mild symptomsof the disease, it is difficult to diagnose and subclinicalinfections are common. However, these subclinical infectionsdo give rise to immunity. For planning and control, it is importantfor public health authorities to estimate the true number ofpeople who have contracted the disease and to assess the impactof key epidemiological parameters. A mathematical model wasdeveloped to describe the transmission of RR virus between itshosts (humans and kangaroos) and its vectors (mosquitoes). Forthis model, the threshold conditions and relative removal rateswere calculated and interpreted. Finally, a computer programwas written to simulate the model in order to estimate the totalnumber, both clinical and sub clinical human infections givenknown and hypothetical epidemiological parameter values. Withinthis simulation sensitivity of the results to changes in theparameters were examined. The analysis of the threshold conditionsconformed well to established principles of arboviral transmissionand control. It was observed that conditions which can preventan outbreak occurring include reducing the number of susceptiblesin host and vector populations, reducing the infection ratesbetween hosts and vectors and shortening the duration of viraemia.Results on the sensitivity analysis showed that some parameterssuch as the extrinsic incubation period, mosquito mortalityrate in winter and the proportion of Western Grey Kangaroosin the marsupial population have little effect on human incidence.However, the transmission rate between hosts and vectors, vector-mortalityrate in summer and the proportion of infectious vectors amonginfected vectors have pronounced effects. The simulation resultson the ratio of clinical to subclinical human infections predicteda minimum ratio of 1:2 and a maximum ratio of 1:65, which isconsistent with data obtained during previous sero-epidemiologicalstudies.     

Bovine lactoferrin inhibits Japanese encephalitis virus by binding to heparan sulfate and receptor for low density lipoprotein

Lactoferrin is a natural anti-microbial protein which affects Japanese encephalitis virus (JEV) activity. Binding of lactoferrin to cell surface expressed heparan sulfate (HS), one possible receptor for JEV, has been postulated to be the possible mechanism of anti-JEV antiviral activity. In this study, we evaluate the effects of bovine lactoferrin (bLF) against JEV infection in vitro, using both wild-type (WT) and laboratory-adapted strains. bLF inhibited the infectivity of all the JEV strains tested. In particular the infectivity of the HS-adapted JEV strains was strongly reduced, whereas the non HS-adapted JEV strains were inhibited to lesser extent. Using both HS-adapted CJN-S1 and non HS-adapted CJN-L1 viruses, the results showed that bLF inhibited the early events essential to initiate JEV infection, which includes blocking virus attachment to cellular membranes and reducing viral penetration. This anti-JEV activity was the highest using HS-adapted CJN-S1 strain on HS-expressed CHO-K1 cells. Also, binding of bLF to heparin-sepharose blocked JEV binding; and soluble HS attenuated the anti-JEV activity of bLF. The results support the premise that the interaction of bLF with cell surface expressed glycosaminoglycans, in particular the highly sulfated HS, plays an essential role in the antiviral activity of bLF. However, bLF was functional in inhibiting CJN-S1 entry into HS-deficient CHO-pgsA745 cells, and bLF-treated CHO-K1 and -pgsA745 cells also prevented non HS-adapted CJN-L1 virus entry, indicating that a non-HS pathway may be involved in bLF inhibition of JEV entry. The low-density lipoprotein receptor (LDLR), possibly involved in the entry of several RNA viruses, also binds to bLF. We found that both rLDLR and anti-LDLR antibodies reduced the effectiveness of bLF inhibition of JEV infection. This finding provided evidence to suggest that cell surface-expressed LDLR may play a role in JEV infection, especially for non HS-adapted strains.