The University of Newcastle, Australia

Experimental models of disease

Dr Jay Horvat's preclinical research is cementing a scientific, nuanced understanding of our bodies' harmful and helpful immunological processes

Jay Horvat

Dr Jay Horvat does his homework. He's using novel experimental models to fact check and fault-find, taking clinical observations and recapitulating them in smaller simulations to dissect and study the intricate architecture of multiple illnesses. Informing the development of innovative and preventative therapeutic treatments, this committed researcher stresses it's the endgame that's important.

"The whole point is to discover molecular mechanisms in experimental models of disease that might similarly be occurring in human patients," he explains.

"This allows us to find new therapeutic targets for the development of treatment strategies that will hopefully translate into improved clinical outcomes for patients with a variety of diseases."

Spanning the microbiological, immunological and pharmacological fields, Jay's work has a particular emphasis on illustrating the roles played by bacteria and viruses in the pathogenesis of acute inflammatory conditions. Mindful of the profound economics of chronic diseases, particularly those with ill-defined triggers, variable clinical courses and not-yet-understood symptoms, this energetic investigator's research is also serving to help construct a "big picture."

"Infection-induced illnesses still cause immense mortality and place an enormous burden on healthcare systems," Jay notes.

"This leads to unsustainable personal and societal costs."

Joining the dots

Jay started his research career with a PhD at the University of Newcastle in 2004. Under the leadership of Professor Phil Hansbro, the four-year probe sought to solidify links between respiratory chlamydia and severe asthma.

"The latter is a major unmet clinical need," he affirms.

"Patients tend to be insensitive to anti-inflammatory steroid therapies so they're usually on higher doses of medications, which could have long-term negative effects."

"Patients are in and out of hospital more often and experience more frequent and extreme exacerbations too."

"They have a lower quality of life."

Appreciating the significance of these health and social impacts, Jay looked to identify how and why severe asthma develops both early on and later in life. He also aimed to confirm hypotheses that major infections drive the disease's most acute forms.

"We found that having a Chlamydia lung infection as either a neonatal or an infant leads to severe changes in lung function as well as more severe asthma," Jay reveals.

"The neonatal infection, in particular, leads to a form of disease that resembles emphysema."

Additionally providing evidence for the existence of a phenotype switch in adults who are infected while they have asthma, Jay's doctoral research highlighted a new association between a different series of immune responses and severe, steroid-insensitive asthma.

"Eosinophils have been classically aligned with asthma," he says.

"They come into the lung during an allergic flare-up and release a variety of inflammatory mediators that can cause you to have an asthma attack."

"If you get certain infections, however, you may get neutrophils coming into the lung instead."

"The processes that drive this type of inflammation are not as easily treated."

"So the infection is causing a shift from a type of immune response that is able to be suppressed by steroids to one that is not."

Better breathing

Jay has continued collaborating with Phil Hansbro post-PhD, actively participating in a number of other asthma projects at the Hunter Medical Research Institute. An extension of his earlier work, these studies explore several bacterial and viral infections and their ties to the disease's more severe forms.

"We've shown that both Chlamydia and Haemophilus influenzae infections drive a neutrophilic subtype of asthma and that influenza and respiratory syncytial virus do not," the senior lecturer states.

"All four, however, similarly drive inflammation and lung function changes that cannot be treated with steroids."

"So we've got four infections doing slightly different things but having this universal effect of driving steroid-resistant inflammation and airway side responsiveness."

Simultaneously identifying a handful of cytokines associated with severe asthma, Jay's examination operates – and succeeds – on the proviso that if you can target a critical factor, you can meaningfully treat disease.

"Cells produce cytokines, which are basically signaling molecules that link cells up and allow them to talk to each other," he clarifies.

"They come out of the lung during an inflammatory response and tell the systemic immune response to mobilise and bring certain cells into the lung as well."

"Interleukin-1 beta is one we've found to be involved in this process."

"It's also one that's able to be depleted with antibodies, which actually suppresses the neutrophilic phenotype where steroids can't."

Looking to expand upon this knowledge, Jay's laboratory work focuses on molecular elements upstream of the newly discovered cytokine.

"A series of molecules, collectively called the 'inflammasome,' need to be activated in order for interleukin 1 beta to be secreted by cells," he says.

"If we intervene, we can stop its production and develop novel therapies for severe asthma."

"The same can be said about a novel micro-RNA we recently found."

In another offshoot of his doctoral research, Jay is surveying the effects of oxidative stress on the progression of infection-induced disease. Pointing to vitamin E as a viable, inexpensive therapeutic option, the ambitious academic is perhaps as cutting-edge as he is creative.

"If we can use this compound to treat severe asthma in early life, we can suppress all of the problems it causes later in life," he comments.

"It's quite exciting because vitamin E is something you can get from the local chemist or grocery store – it's already approved for general consumption."

Branching out and stepping up

A master at multitasking, Jay is currently working on some of his own independent research programs.

"Our most advanced one looks at how certain inflammatory stresses might affect Alzheimer's," he discloses.

"We're also examining the effect smoking has on neurodegenerative processes."

Jay and his team are hoping to uncover clues as to how and why the disease advances using their experimental models. They're similarly hoping to develop therapies that will stop or reverse it's progression.

"Chlamydia bacteria has been found in plaques of the brains of patients with Alzheimer's," he shares of the initial findings.

"We have extended these findings to show that infections enter the brain during our models of respiratory infection."

"So the infection can get into the brain – and if it can do this, it could be doing all sorts of things to affect the progression of Alzheimer's."

"We have also shown that cigarette smoking accelerates the number and size of the plaques in the brain."

Extending his research interests even further afield, the Hunter Medical Research Institute innovator is also collaborating with Dr Simon Keely on a novel food allergy project. Marrying Simon's experience in inflammatory bowel disease and Jay's experience with allergy; the study aims to explore and determine the effects of antibiotics on the microbiome and how this may affect immune processes in the gut that predispose to allergic sensitisation to normally harmless food protein.

"Antibiotic use has been linked with increased risk of developing food allergy," Jay explains.

"Importantly, antimicrobials wipe out bacteria throughout the body, especially the gut, and we think this influences immune responses and might predispose to allergic sensitization."

"We show, for example, that taking a five day course of common prescribed antibiotics results in some pretty interesting changes to the immune system in the gut."

"Our hypothesis is that food allergies are dramatically increasing in the developed world because we have a tendency to overtreat bacterial infections, which in turn has an effect on a healthy balanced immune system."

Infection protection

Jay is also collaborating with Professor Liz Milward on a research assignment that looks at the tricky interplay between iron, immune responses and infection in the context of lung disease.

"We want to understand how these three elements come together in the context of the lungs," he explains.

"Literature already tells us that both high and low iron can affect immune responses."

"It also tells us iron is important for bacterial replication."

Jay and Liz are linking a small number of hereditary disorders to this work, looking to identify ways of modifying immune responses through iron and, in doing so, improve treatment options for those suffering from a range of bacterial infections.

"Cystic fibrosis patients have increased levels of iron in their airways and this might be an important reason as to why they're more likely to get chronic colonisation with certain bacteria in the lungs," he acknowledges.

At the same time, Jay is also working with a University of Newcastle PhD student on an adaptation of his earlier respiratory Chlamydia research. This time exploring the role of immune responses in stopping the progression of femalereproductive tract Chlamydia infections, Jay is seeking to develop a comprehensive understanding of the pathogenesis of sexually transmissible infection (STI).

"The immune system in the female reproductive tract is different to other organs as it needs to be able to tolerate the implantation of an embryo that is genetically different from the mother," he comments.

"Consequently, much of what we know about immunity from research of other tissues does not completely apply to the female reproductive tract."

"While Chlamydia is able to be treated with antibiotics, a lot of infections are asymptomatic so you don't go to the doctor to get treated."

Jay explains that if Chlamydia is untreated, it is able to advance into the uterus and fallopian tubes and eventually become chronic. The immune responses elicited in order to protect against this chronic upper reproductive tract infection, can cause damage to the delicate tissues in the female reproductive tract, and this can result in serious problems including infertility, pelvic inflammatory disease and ectopic pregnancy.

"We are trying to identify the protective immune factors, and those that cause damage, so that we can develop improved therapeutic strategies for preventing and treating disease," he shares.

"In collaboration with researchers at Monash University we have identified a novel type 1 interferon that protects against infection in the female reproductive tract."

"We are currently working with this factor to try to come up with innovative therapies for Chlamydia."

"These might be applicable to other STIs, like human papillomavirus, herpes and HIV."

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