Q&A: Research focuses on mechanisms of mpox infection, potential ocular manifestations
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Key takeaways:
- The WHO declared mpox a public health emergency of international concern.
- Mpox-related ophthalmic disorders have been observed.
On Aug. 14, the WHO declared the clade I mpox virus outbreak in Africa to be a public health emergency of international concern.
The next day, the first case outside Africa, identified as clade Ib, was reported by health authorities in Sweden. Clade I appears to spread more easily from human to human, have a higher fatality rate and more frequently be the cause of mpox-related ophthalmic disorders.
In this interview with Healio | OSN, Vaithilingaraja Arumugaswami, DVM, PhD, professor of molecular and medical pharmacology at UCLA, and Ashok Kumar, PhD, professor of ophthalmology, microbiology and immunology at Wayne State University School of Medicine in Detroit, overviewed the mechanisms of action of the mpox virus (MPXV), its manifestations in the eye, and the research being done to better understand and fight the disease.
Healio: The WHO, together with the Africa CDC, declared mpox a public health emergency of international concern. What has changed since the previous outbreak in 2022, and what might be expected?
Arumugaswami: We have known the mpox virus since the 1970s, when it was detected for the first time in a baby in Africa. Mpox is closely related to smallpox, and the massive smallpox eradication effort in course at the time also kept mpox under control. Since the smallpox vaccination program stopped, the current population is mostly less immune, and MPXV has had time to slowly accumulate mutations. This explains why in the past 10 years the virus has been smoldering in the Democratic Republic of the Congo (DRC).
There are currently two clades of MPXV, and both were detected in Congo. In 2022, clade IIb expanded globally, and that wave of mpox outbreak is still ongoing. But now we have clade I, which added more mutations and started spreading outside Congo in neighboring countries that had not reported mpox before. With modern air travel, the virus can spread faster. Outside of Africa, it is limited for now, but when you start seeing an outbreak, that is only the tip of the iceberg, and there is already a massive undercurrent of infection ongoing. Then you start seeing the people who are susceptible, and in coming days or even coming hours, you start seeing more reports throughout the world. The new clade I is almost close to smallpox, but the severity is higher than clade II, with a 10% mortality rate. It kills more women and children, who are disproportionately affected, and we do not know why. Is there a hormone effect? Are the children’s immune systems not strong enough to handle it? Is it malnutrition? Another established mode of spread right now is between heterosexual partners. It is no longer the men who have sex with men population, as it was with the previous clade. However, MPXV is not as contagious as SARS-CoV-2, which could be transmitted by a just a puff of breath in a room or airplane. This virus is transmitted if there is close contact with the person you are speaking or breathing with or, most likely, when you have intimate skin contact. Therefore, the transmission may be more limited. Having said that, we know that viruses mutate and do so to get better at spreading among humans.
Healio: With more than 18,000 suspected cases and 629 deaths reported in the DRC this year, according to WHO, clade I seems to be spreading more rapidly compared with clade II. What is fueling the spread of the virus?
Kumar: We don’t have a clear answer right now, but we suspect there is probably some sort of mutation happening in clade I. We need sequencing information of currently spreading clade Ib strains, and only then can we do a deeper analysis to understand what kind of functional mutations are out there. Functional mutations are those through which viruses acquire new genes or even subtle genetic change that allow them to replicate more, infect more, adapt better, enter multiple cell types and spread quickly. In the lab, we sequenced clade IIb and found 21 to 22 gene mutations. Right now, we don’t know the function, but we are studying them. We make the strain mutate, remove those genes in laboratory condition and then see what happens to the virus. Does it become more or less infectious? In this way, we can understand the functionality of those new gene variants. Some gene variants may have no effect, or maybe we don’t know their effect yet.
Arumugaswami: To add to that, MPXV belongs to the orthopoxvirus group, a family of viruses that includes smallpox and cowpox, as well as others. When you compare the genes of these viruses, if you align them, there are about 200 genes, but the genes on the terminal regions of the genome sometimes disappear, or there are new genes coming in. Those are the ones giving the new characteristic to that particular strain. The genes in the center of the genome are like housekeeping genes: They are always there, and they are required for virus survival. But the genes in the terminal regions are actually contributing to the new virulence. Also, they are good at making the virus hide in our body without our immune system detecting them. So, these are the genes we are looking at.
The current clade I is a select agent because it is considered close to smallpox. Select agents are pathogens for which there is no known cure and can potentially be weaponized. They are subject to stringent regulatory requirements, so we are not yet allowed to export clade Ib from Congo to study it in the lab. This is a limitation, and we are now working mainly with clade II. MPXV is a stealth-adapted virus. This means that it can bypass the cellular immune defense mechanisms efficiently. We are doing studies to see what genes are involved in this kind of stealth mode. The next step will be to see if we can remove those genes so that the human host can sense the virus and stop or slow down its replication. Lower-level replicating viruses can also be specifically developed for a vaccine specific for mpox.
Healio: Your group recently published a review, “Mpox virus and its ocular surface manifestations.” What were your findings? How does mpox affect the eye?
Kumar: Besides the typical cutaneous symptoms and the more general symptoms such as headache, fever and lymphadenopathy, we are seeing cases of ocular manifestations, collectively termed as mpox-related ophthalmic disorders. We recently published the review, and we have also established experimental models to study ocular mpox that have not been published yet. The first sign that the eye has been infected is a pimple, a papule-like structure on the eyelid. From there, the virus can infect and replicate on the conjunctiva and cornea, causing inflammation and other changes.
Our hypothesis is that patients mainly infect the eye through autoinoculation, which occurs if they have a rash on their skin or in the genital region, touch the infected area and then somehow touch their eyes. Once the virus is on the ocular surface, it can cause multiple complications. One common complication is pustules on the eyelids and eyelid edema. Conjunctivitis is also quite common, but the most severe, sight-threatening condition is keratitis. The corneal epithelial cells become infected, and then the infection goes deeper into the stroma, just like herpes keratitis. Cases of anterior uveitis, conjunctival erosion, corneal ulcers and corneal opacification have been reported. Some patients also develop granulomatous precipitates in the anterior chamber. These cases were seen during the 2022 outbreak, we reviewed them, and this inspired us to do more. We went back from bedside to bench to investigate basic disease mechanism. We developed an animal model, and we are also working ex vivo on donor corneas to understand the underlying pathogenic mechanisms and potentially develop new targeted treatments. As current understanding of ocular mpox is limited to clinical reports with little insight into its pathogenesis, our ongoing studies will fill a knowledge gap by determining viral and host factors contributing to ocular manifestations of mpox.
Healio: What do we currently have and what is in the pipeline in terms of potential treatments?
Arumugaswami: TPOXX (tecovirimat, Siga), which is an FDA-approved treatment for smallpox, has shown promising results in the recent studies in which it was used for mpox. However, systematic large-scale clinical trials are pending. While the drug was relatively effective against the previous MPXV strain, the newly circulating strains might not respond to this drug. Similarly, the smallpox vaccine showed approximately 85% effectiveness with the previous strain of mpox, but we don’t know how effective it might be with the current one. In our lab, we are now doing drug screening with thousands of compounds and multiple concentrations, testing their efficacy against MPXV in corneal cells. We are seeing encouraging outcomes, and we are doing fundraising from governments and private donors because more research is needed. These epidemics are periodical, and once they are over, people tend to forget. Smallpox killed 400 million people in 100 years, and then we forgot, as if nothing had happened. When an outbreak is over, people no longer want to invest money and resources. But the virus, meanwhile, is quietly mutating and preparing for us. Humanity must be constantly aware of this threat, or at least government agencies should be. We need a concerted effort with an investment in more resources to understand this virus better.
References:
- Chakravarty N, et al. Ocul Surf. 2024;doi:10.1016/j.jtos.2024.07.001.
- UNICEF issues emergency tender to secure mpox vaccines for crisis-hit countries in collaboration with Africa CDC, Gavi and WHO. https://www.who.int/news/item/31-08-2024-unicef-issues-emergency-tender-to-secure-mpox-vaccines-for-crisis-hit-countries-in-collaboration-with-africa-cdc--gavi-and-who. Published Aug. 31, 2024. Accessed Sept. 9, 2024.
For more information:
Vaithilingaraja Arumugaswami, DVM, PhD, of UCLA, can be reached at varumugaswami@mednet.ucla.edu.
Ashok Kumar, PhD, of Wayne State University School of Medicine in Detroit, can be reached at akuma@med.wayne.edu.
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