Disease Tolerance during Viral-Bacterial Co-Infections

Disease tolerance has emerged as an alternative way, in addition to host resistance, to survive viral-bacterial co-infections. Disease tolerance plays an important role not in reducing pathogen burden, but in maintaining tissue integrity and controlling organ damage. A common co-infection is the synergy observed between influenza virus and Streptococcus pneumoniae that results in superinfection and lethality. Several host cytokines and cells have shown promise in promoting tissue protection and damage control while others induce severe immunopathology leading to high levels of morbidity and mortality. The focus of this review is to describe the host cytokines and innate immune cells that mediate disease tolerance and lead to a return to host homeostasis and ultimately, survival during viral-bacterial co-infection

Sequential targeting of interferon pathways for increased host resistance to bacterial superinfection during influenza.

Bacterial co-infections represent a major clinical complication of influenza. Host-derived interferon (IFN) increases susceptibility to bacterial infections following influenza, but the relative roles of type-I versus type-II IFN remain poorly understood. We have used novel mouse models of co-infection in which colonizing pneumococci were inoculated into the upper respiratory tract; subsequent sublethal influenza virus infection caused the bacteria to enter the lungs and mediate lethal disease. Compared to wild-type mice or mice deficient in only one pathway, mice lacking both IFN pathways demonstrated the least amount of lung tissue damage and mortality following pneumococcal-influenza virus superinfection. Therapeutic neutralization of both type-I and type-II IFN pathways similarly provided optimal protection to co-infected wild-type mice. The most effective treatment regimen was staggered neutralization of the type-I IFN pathway early during co-infection combined with later neutralization of type-II IFN, which was consistent with the expression and reported activities of these IFNs during superinfection. These results are the first to directly compare the activities of type-I and type-II IFN during superinfection and provide new insights into potential host-directed targets for treatment of secondary bacterial infections during influenza

Efficacy of linezolid against Staphylococcus aureus in different rodent skin and soft tissue infections models

Linezolid is approved for complicated and uncomplicated skin and soft tissue infections. We have evaluated the efficacy of this drug in murine as well as in rat skin and soft tissue infection models using Staphylococcus aureus ATCC and clinical strains. In thigh infection model the dose of linezolid required for more than 1 log10 kill from baseline inoculum in neutropenic mice and rats was 100 mg/kg and 50 mg/Kg BW bid /day, respectively, which was 5 and 4 folds more than that in immunocompetent animals, respectively. Dose required to achieve 1 log10 killing was similar against different strains of S. aureus in immunocompetent mouse thigh infection model. However, in murine groin abscess infection model, a dose of 100 mg/kg, b.i.d/day of linezolid produce static effect in 2 days, but revealed to be superior in 4 days treatment and showed approximately 1 log10 killing from base line inoculums. Based upon pharmacokinetic profile, a 24-h AUC/MIC required for linezolid efficacy in murine groin abscess model was 91.5 for the strain used in this study. As linezolid is taken as a gold standard drug in the evaluation of new chemical entity, this data could be useful for comparing the preclinical efficacy of new anti-MRSA agents.</p

<i>Cissampelos pareira</i> Linn: Natural Source of Potent Antiviral Activity against All Four Dengue Virus Serotypes

<div><p>Background</p><p>Dengue, a mosquito-borne viral disease, poses a significant global public health risk. In tropical countries such as India where periodic dengue outbreaks can be correlated to the high prevalence of the mosquito vector, circulation of all four dengue viruses (DENVs) and the high population density, a drug for dengue is being increasingly recognized as an unmet public health need.</p><p>Methodology/Principal findings</p><p>Using the knowledge of traditional Indian medicine, Ayurveda, we developed a systematic bioassay-guided screening approach to explore the indigenous herbal bio-resource to identify plants with pan-DENV inhibitory activity. Our results show that the alcoholic extract of <i>Cissampelos pariera</i> Linn (<i>Cipa</i> extract) was a potent inhibitor of all four DENVs in cell-based assays, assessed in terms of viral NS1 antigen secretion using ELISA, as well as viral replication, based on plaque assays. Virus yield reduction assays showed that <i>Cipa</i> extract could decrease viral titers by an order of magnitude. The extract conferred statistically significant protection against DENV infection using the AG129 mouse model. A preliminary evaluation of the clinical relevance of <i>Cipa</i> extract showed that it had no adverse effects on platelet counts and RBC viability. In addition to inherent antipyretic activity in Wistar rats, it possessed the ability to down-regulate the production of TNF-α, a cytokine implicated in severe dengue disease. Importantly, it showed no evidence of toxicity in Wistar rats, when administered at doses as high as 2g/Kg body weight for up to 1 week.</p><p>Conclusions/Significance</p><p>Our findings above, taken in the context of the human safety of <i>Cipa</i>, based on its use in Indian traditional medicine, warrant further work to explore <i>Cipa</i> as a source for the development of an inexpensive herbal formulation for dengue therapy. This may be of practical relevance to a dengue-endemic resource-poor country such as India.</p></div

Analysis of interaction between paracetamol and <i>Cipa</i> extract.

<p>(A) DENV-3 (50 PFU) was pre-incubated with <i>Cipa</i> extract in the absence (solid black diamonds) or presence of 1 μg/ml (solid blue diamonds), 10 μg/ml (solid red circles), or 100 μg/ml (solid green circles) paracetamol overnight at 4°C, followed by analysis of viral inhibition in a type-1 assay. (B) Febrile Wistar rats were mock-treated (empty red circles), or treated with paracetamol (solid blue circles), <i>Cipa</i> extract (empty green squares) or a combination of both (solid black squares), followed by monitoring of rectal temperature for 3 hours post-treatment at regular intervals. Rectal temperatures between the control (mock-treated) and treatment groups were compared using one-way ANOVA followed by Dunnett’s multiple comparison test (the single and double stars indicate significant differences in the treatment groups with respect to the control group, corresponding to <i>p</i> values of ≤0.05 and ≤0.01, respectively).</p