A pinboard by
Mithun Das

Ph.D. Candidate, La Trobe University


Understand host defence system, and plot your enemy’s demise by introducing trained armies

Virus infections remain one of the major causes of human morbidity and mortality. For many viral infections, there is no effective therapy, and in the low economic countries most of the times vaccines and expensive therapies remain inaccessible. Therefore, it is necessary to develop safe, effective and inexpensive therapies to treat viral infections. By considering these facts, scientists are currently thinking about using the self defense system to control deleterious viral infections. Implementation of this unique concept is at very primary level and extensive studies are necessary to understand how the antiviral defense system works at the cellular level, what factors are involved, and what mechanisms cells use to control viral infections.

Viruses are a major cause of infections, resulting damaging effect in our body by causing major pathophysiological complications. However, interestingly, some of the cells in our body such as astrocytes, macrophages, etc. have decreased viral load and can evade cell death during many viral infections such as Human immunodeficiency virus (HIV), Herpes virus, Japanese encephalitis (JEV), West Nile virus (WNV), etc., but their survival remains mostly unexplained. In order to understand the mechanisms of their survival, I am designing a genome screening approach to identify cellular factors involved in antiviral responses, which can potentially be novel therapeutic targets.

How will we use this knowledge of exceptional abilities of the antiviral immune cells, such as astrocytes, macrophages for the development of novel therapies?

The attained knowledge about the abilities of novel host factors in the virus resistant cells, and how these factors modulate immune responses to control viral infections will be used to design therapies to regulate host immune responses during viral infections. These therapies will potentially target not only the cells that are resistant to viral infections but also in susceptible cells. The findings of this study will present a new way to design antiviral therapies that are ultimately cost-effective yet resilient against variety of viral infections.

This pinboard designed to inform you about not only our research, but also the current study trends in revealing the facts of the human primary defense system and therefore, identify therapeutic targets and develop novel immune therapeutic approaches to treat viral infections.


Alveolar macrophages are essential for protection from respiratory failure and associated morbidity following influenza virus infection.

Abstract: Alveolar macrophages (AM) are critical for defense against bacterial and fungal infections. However, a definitive role of AM in viral infections remains unclear. We here report that AM play a key role in survival to influenza and vaccinia virus infection by maintaining lung function and thereby protecting from asphyxiation. Absence of AM in GM-CSF-deficient (Csf2-/-) mice or selective AM depletion in wild-type mice resulted in impaired gas exchange and fatal hypoxia associated with severe morbidity to influenza virus infection, while viral clearance was affected moderately. Virus-induced morbidity was far more severe in Csf2-/- mice lacking AM, as compared to Batf3-deficient mice lacking CD8α+ and CD103+ DCs. Csf2-/- mice showed intact anti-viral CD8+ T cell responses despite slightly impaired CD103+ DC development. Importantly, selective reconstitution of AM development in Csf2rb-/- mice by neonatal transfer of wild-type AM progenitors prevented severe morbidity and mortality, demonstrating that absence of AM alone is responsible for disease severity in mice lacking GM-CSF or its receptor. In addition, CD11c-Cre/Ppargfl/fl mice with a defect in AM but normal adaptive immunity showed increased morbidity and lung failure to influenza virus. Taken together, our results suggest a superior role of AM compared to CD103+ DCs in protection from acute influenza and vaccinia virus infection-induced morbidity and mortality.

Pub.: 05 Apr '14, Pinned: 18 Sep '17

Efficacy of antiviral compounds in human herpesvirus-6-infected glial cells.

Abstract: The beta-herpesvirus human herpesvirus-6 (HHV-6) is becoming increasingly recognized as an important pathogen in immunocompromised patients, particularly in post bone marrow transplant (BMT). Reactivation of latent HHV-6 resulting in encephalitis has been reported in BMT and stem cell transplant (SCT) patients. The development of HHV-6 encephalitis can be a fatal complication, the frequency of which is increasing likely due to improved diagnosis with quantitative polymerase chain reaction (PCR) of cerebrospinal fluid. There are currently no antiviral compounds approved for HHV-6, nor have any controlled clinical trials been conducted. The frequency and severity of HHV-6 encephalitis in both immunocompetent and immunocompromised patients necessitates studies on the usefulness of currently available anti-viral compounds. The authors compared the antiviral efficacy of four drugs currently used for cytomegalovirus (CMV) infection, a beta-herpesvirus sharing homology with HHV-6. In HHV-6A- and HHV-6B-infected T cells, acyclovir, ganciclovir, foscarnet, and cidofovir exhibited antiviral activity consistent with that published in other studies. In HHV-6-infected human astrocytes (U251), however, only foscarnet and cidofovir exhibited antiviral activity and this effect was restricted to infection with HHV-6 variant A. In pathological brain sections from patients with neurological disorders such as multiple sclerosis and epilepsy, HHV-6 has been localized to glial cells. Determination of antiviral activity in human glial fibrillary acidic protein (GFAP)-positive astrocytes of currently used antiviral compounds is essential for potential treatment of HHV-6 and neurological disorders. Our data highlight the necessity for further study of antiviral compound in HHV-6-infected glial cells as well as the development of more selective compounds for HHV-6.

Pub.: 13 Sep '06, Pinned: 18 Sep '17

Astrocyte indoleamine 2,3-dioxygenase is induced by the TLR3 ligand poly(I:C): mechanism of induction and role in antiviral response.

Abstract: Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan catabolism and has been implicated in neurotoxicity and suppression of the antiviral T-cell response in HIV encephalitis (HIVE). Here we show that the Toll-like receptor 3 (TLR3) ligand poly(I:C) (PIC) induces the expression of IDO in human astrocytes. PIC was less potent than gamma interferon (IFN-gamma) but more potent than IFN-beta in inducing IDO. PIC induction of IDO was mediated in part by IFN-beta but not IFN-gamma, and both NF-kappaB and interferon regulatory factor 3 (IRF3) were required. PIC also upregulated TLR3, thereby augmenting the primary (IFN-beta) and secondary (IDO and viperin) response genes upon subsequent stimulation with PIC. In HIVE, the transcripts for TLR3, IFN-beta, IDO, and viperin were increased and IDO immunoreactivity was detected in reactive astrocytes as well as macrophages and microglia. PIC caused suppression of intracellular replication of human immunodeficiency virus pseudotyped with vesicular stomatitis virus G protein and human cytomegalovirus in a manner dependent on IRF3 and IDO. The involvement of IDO was demonstrated by partial but significant reversal of the PIC-mediated antiviral effect by IDO RNA interference and/or tryptophan supplementation. Importantly, the cytokine interleukin-1 abolished IFN-gamma-induced IDO enzyme activity in a nitric oxide-dependent manner without suppressing protein expression. Our results demonstrate that IDO is an innate antiviral protein induced by double-stranded RNA and suggest a therapeutic utility for PIC in human viral infections. They also show that IDO activity can be dissociated from protein expression, indicating that the local central nervous system cytokine and nitric oxide environment determines IDO function.

Pub.: 13 Jul '07, Pinned: 18 Sep '17

NK cells in hepatitis B virus infection: a potent target for immunotherapy.

Abstract: Viruses, including hepatitis B virus (HBV), are the most prevalent and infectious agents that lead to liver disease in humans. Hepatocellular carcinoma (HCC) and cirrhosis of the liver are the most serious complications arising from prolonged forms of hepatitis B. Previous studies demonstrated that patients suffering from long-term HBV infections are unable to eradicate HBV from hepatocytes completely. The mechanisms responsible for progression of these forms of infection have not yet been clarified. However, it seems that there are differences in genetic and immunological parameters when comparing patients to subjects who successfully clear HBV infections, and these may represent the causes of long-term infection. Natural killer (NK) cells, the main innate immune cells that target viral infections, play important roles in the eradication of HBV from hepatocytes. NK cells carry several stimulatory and inhibitor receptors, and binding of receptors with their ligands results in activation and suppression of NK cells, respectively. The aim of this review is to address the recent information regarding NK cell phenotype, functions and modifications in hepatitis B. This review addresses the recent data regarding the roles of NK cells as novel targets for immunotherapies that target hepatitis B infection. It also discusses the potential to reduce the risk of HCC or cirrhosis of the liver by targeting NK cells.

Pub.: 22 Jan '14, Pinned: 18 Sep '17