December 06, 2024
4 min read
Click here to read the Cover Story, “Specialists address challenges of microbial keratitis management.”
Addressing bacteria
There are two lines of research we are pursuing in our lab currently.
The first is phage therapy, a strategy that is approved in Europe and used as an alternative to antibiotics in other fields of medicine, mainly for skin infections. Phages are viruses that infect the bacteria and through the production of specific enzymes — the endolysins — kill them from within. In 2014, we showed in our lab the efficacy of phage endolysin therapy for intraocular infections, namely endophthalmitis. Our findings were confirmed by further research done by the Callegan Lab in Oklahoma, which also published the positive results of phage lysins administered topically in an experimental keratitis model. Phage therapy could be a game changer for the treatment of corneal infections, particularly against antibiotic-resistant pathogens.
The use of live phage therapy often met with skepticism with concerns that live phages, while killing the bacteria, may cause side effects in the eye. While this needs to be tested, the good thing about phages is that they need bacteria for their survival and keep proliferating until they have eaten up every single bacterium. At that point, once the last bacterium is dead, they can no longer survive. Therefore, they can do no harm.
Our second line of research is drug repurposing — that is, the identification of new targets for drugs that are already in use for other indications. For instance, a drug that has been used for cancer or Alzheimer’s disease may have some antimicrobial activity that can be explored. In our lab we developed a C-mapping approach, using the Connectivity Map database, which comprises more than 7,000 genomic profiles corresponding to 1,309 small bioactive molecules and FDA-approved drugs. We infect the cells of an animal model or human tissue and do transcription profiling to have the full information about the gene expression of the tissue under those pathological conditions. Then we run the transcriptomic profiles of the infected tissues against the drug profiles to identify the molecules that are able to reverse the dysregulated gene expression. We did this for bacterial endophthalmitis, but the same process could be applied to other infectious diseases. This approach looks promising and cost-effective because it uses drugs that are already developed and commonly used. It could also be a strategy to find alternatives to antibiotic therapy, another way to address the problem of antimicrobial resistance.
- References:
- Das S, et al. iScience. 2022;doi:10.1016/j.isci.2022.104862.
- Mursalin MH, et al. mSphere. 2023;doi:10.1128/msphere.00044-23.
- Singh S, et al. Cell Rep Med. 2021;doi:10.1016/j.xcrm.2021.100277.
- Singh S, et al. Infect Immun. 2023;doi:10.1128/iai.00252-22.
- Singh S, et al. J Immunol. 2024;doi:10.4049/jimmunol.2400282.
Ashok Kumar, PhD, professor of ophthalmology, microbiology and immunology at Wayne State University of Medicine in Detroit, can be reached at akuma@med.wayne.edu.
Addressing viruses
Viral pathogens are a significant category of infectious agents affecting the ocular surface.
It is well established that pathogens such as herpes simplex and varicella-zoster viruses — and, to a lesser extent, HIV — can affect the cornea, leading to vision-threatening ocular complications. In addition, emerging and reemerging viral pathogens, such as mpox and Ebola viruses, pose a clear and present danger to public health as they can infect ocular surface tissues and cause corneal ulcers and band keratopathy. The incidence of viral eye diseases is significantly underreported due to a lack of proper diagnosis. Identifying novel and emerging pathogens is challenging, necessitating an unbiased approach to utilize modern technologies for detecting the “microbiome” content in healthy and diseased eyes. As far as treatment is concerned, we also face significant challenges, as only a few viruses, such as herpes and HIV, can be effectively treated with timely diagnosis. Additionally, viruses are adept at developing resistance to existing treatments. Therefore, it is imperative to push for advancements in antiviral development so that emerging viruses, such as mpox and Ebola, can be effectively addressed in both ocular and systemic contexts.
In our lab, we are currently focusing on the mpox virus (MPXV). The outbreak is still simmering: New cases have been reported in the United Kingdom, India and Germany, and those are just the tip of the iceberg. TPOXX (tecovirimat, Siga), a drug for smallpox, showed some efficacy against mpox in the previous 2003 outbreak, but viruses mutate, and the new strains may no longer respond to it. In our lab, we have been performing high throughput drug screening using a library of about 5,000 compounds and multiple concentrations, testing their efficacy as a host-targeted strategy against MPXV in corneal cells. We recently got institutional approval for testing five of these compounds that have shown to act against the mpox virus targeting the host cell machinery, and for those we are progressing to animal studies.
There are other emerging viruses, such as Lassa fever, Marburg and Rift Valley fever viruses, that also cause anterior segment eye disease. The challenge in studying these viruses is that they all require high-containment biological laboratories because there is no existing treatment for them. Many of us regular researchers in the university will not have access to these high-containment facilities and need to work with government agencies, such as the U.S. military or NIH, to study these viruses. But we are developing a surrogate system, a less virulent or simplified system, so that we can study or develop drugs against these viruses in a regular laboratory condition. Taken together, it is imperative to develop medical countermeasures against these pathogens to ensure better preparedness during future outbreaks.
- Reference:
- Chakravarty N, et al. Ocul Surf. 2024;doi:10.1016/j.jtos.2024.07.001.
Vaithilingaraja Arumugaswami, DVM, PhD, professor of molecular and medical pharmacology at UCLA, can be reached at varumugaswami@mednet.ucla.edu.
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