Infectious diseases caused by microorganisms are still major causes of death all over the world and the increasing number of their resistant strains results in great concerns. Since the discovery of gene silencing using RNA interference (RNAi), there has been a revolution in its medical applications. By using RNAi, proliferation and progression of viral, bacterial, and parasitic infections such as the HIV virus, hepatitis C virus (HCV), SARS virus, hepatitis B virus (HBV), Ebola virus, methicillin resistant Staphylococcus aureus (MRSA), Mycobacterium tuberculosis, Francisella tularensis, and protozoa and helminthes parasites are prevented. RNAi-based gene therapies have become more and more interesting and promising. This study has reviewed various therapeutic characteristics of RNAi, especially its therapeutic characteristics on human infectious diseases.

Application of RNA Interference (RNAi) in The Treatment of Human Infectious Diseases

Using mce4 siRNA molecular beacons for detection and eradication of mycobacterial infection in macrophages

Tuberculosis is one of the leading infectious diseases plaguing mankind and is mediated by the facultative pathogen, Mycobacterium tuberculosis (MTB). Once the pathogen enters the body, it subverts the host immune defenses and thrives for extended periods of time within the host macrophages in the lung granulomas, a condition called latent tuberculosis (LTB). Persons with LTB are prone to reactivation of the disease when the body's immunity is compromised. Currently there are no reliable and effective diagnosis and treatment options for LTB, which necessitates new research in this area. The mycobacterial proteins and genes mediating the adaptive responses inside the macrophage is largely yet to be determined. Recently, it has been shown that the mce operon genes are critical for host cell invasion by the mycobacterium and for establishing a persistent infection in both in vitro and in mouse models of tuberculosis. The YrbE and Mce proteins which are encoded by the MTB mce operons display high degrees of homology to the permeases and the surface binding protein of the ABC transports, respectively. Similarities in structure and cell surface location impute a role in cell invasion at cholesterol rich regions and immunomodulation. The mce4 operon is also thought to encode a cholesterol transport system that enables the mycobacterium to derive both energy and carbon from the host membrane lipids and possibly generating virulence mediating metabolites, thus enabling the bacteria in its long term survival within the granuloma. Various deletion mutation studies involving individual or whole mce operon genes have shown to be conferring varying degrees of attenuation of infectivity or at times hypervirulence to the host MTB, with the deletion of mce4A operon gene conferring the greatest degree of attenuation of virulence. Antisense technology using synthetic siRNAs has been used in knocking down genes in bacteria and over the years this has evolved into a powerful tool for elucidating the roles of various genes mediating infectivity and survival in mycobacteria. Molecular beacons are a newer class of antisense RNA tagged with a fluorophore/quencher pair and their use for in vivo detection and knockdown of mRNA is rapidly gaining popularity.

Use of siRNA molecular beacons to detect and attenuate mycobacterial infection in macrophages.

The ability of the pathogen Mycobacterium Tuberculosis (MTB) to invade and survive within macrophages of granulomas is attributed to the product of the Mammalian Cell Entry (MCE) operon whose gene, mce4A , encodes a cholesterol transporter that transports h ost lipids into the bacterium that allows the bacte rium to survive during chronic infection. Here, we proposed and tested the hypothesis that a mce4A siRNA molecular beacon can be used to attenuate mycobacterial infec tion in macrophages. Mce4A gene was cloned and expressed in E. coli (E. coli-4A ) and differentiated U937 cells were transduced wit h piLenti-siRNA -GFP phage expressing the mce4A siRNA for 24 h. This was followed by infection wit h either E. coli-4A or M. smegmatis for 3 h followed by incubation for 0, 3, 6, 24 and 48 h . The cells were lysed and the lysates were plated on LB agar plates containing ampicillin (100 µg mL -1 ) or on 7H11 media and incubated at 37°C overnight. Our results showed that the siRNA treatment attenuated E.coli-4A infection in macrophages at 3, 6, 24 and 48 h by 0 , 77, 59.6 and 99.7%, respectively. Our results also show ed that the siRNA treatment attenuated M. smegmatis infection in macrophages at 3, 6, 24 and 48 h. by 9 4.8, 70.3, 98.9 and 93.4%, respectively. In conclus ion, a mce4A siRNA molecular beacon was successfully delivered and stably expressed in macrophages which attenuated E. coli expressing mce4A (E. coli-4A) and M. smegmatis infection in macrophages.

A short interfering rna molecular beacon for the attenuation of mycobacterial infection

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A short interfering rna molecular beacon for the attenuation of mycobacterial infection