



When we hear about immunotherapy these days, it’s most often associated with treatments or molecular pathways associated with cancer. But what if these immunological molecules could be exploited to treat one of the deadliest infectious diseases on the planet—malaria. New evidence from researchers at the University of Iowa (UI) Carver College of Medicine shows that targeting an immune checkpoint molecule at the right time during infection allows mice to quickly clear malaria infections. More importantly, the treated mice also develop lasting immunity to the parasitic disease.

Findings from the new study—published recently in Nature Medicine, in an article entitled “Regulatory T Cells Impede Acute and Long-Term Immunity to Blood-Stage Malaria through CTLA-4”—showed that the checkpoint protein called anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is expressed and released by a subset of immune cells called regulatory T cells (Tregs) that are involved in immune suppression of the infection.

“People have long known that malaria is associated with a huge immunosuppressive response, but no one knew the mechanism,” explained lead study investigator Samarchith Kurup, Ph.D., a UI assistant research scientist.

“The CTLA-4 molecule interferes with appropriate immune activation,” added senior study investigator John Harty, Ph.D., a UI professor of microbiology and immunology. “Specifically, it interferes with the function of several types of T helper cells whose job it is to drive immune responses against malaria.”

Close to 50% of the world’s population live in areas endemic for malaria, leading to roughly 200 million cases of malaria each year and almost 500,000 malaria-related deaths—mostly among children under the age of five. Drug resistance is rampant among malaria parasite strains, and researchers continually strive to better understand the mechanisms of infection for this parasite that has plagued human society since the Stone Age.





Malaria prevents the host body (human or mouse) from developing lasting immunity. A new University of Iowa study, led by microbiology professor John Harty, has homed in on a potential culprit of this immunosuppression. The molecule, CTLA-4, is produced by a type of immune cell called a Treg cell. Blocking CTLA-4 at the right time during blood-stage infection allows mice to quickly clear malaria. Importantly, the treated mice also develop lasting immunity to malaria. The video, captured with intravital confocal immunofluorescence microscopy, shows Treg cells (green) delivering CTLA-4 to B-cell (blue/ magenta) helper T cell (red) clusters in the spleen of a mouse. The CTLA-4 molecule inhibits efficient production of antibodies against malaria. If this pathway works in humans as it does in mice, blocking CTLA-4 might be a way to improve malaria treatment and boost immunity to reinfection. The study was published Sept. 11 online in Nature Medicine [Samarchith Kurup/ Scott Anthony/University of Iowa].





In most infectious diseases, a group of immune cells called T helper cells increase in number, cooperate with B cells to make antibodies that clear the infection, and then leave behind memory T and B cells to defend against reinfection with the same pathogen. Unfortunately, this doesn’t always happen with malaria. Instead, there is a period where the T helper cell expansion stalls. During that critical time period, the UI researchers showed that the Treg population increased

“Our observation that the Tregs went up when the T helper cells stopped going up showed a timing relationship that suggested the possibility of a functional relationship,” Dr. Harty noted.

When the UI team eliminated Treg cells in mice with blood-stage malaria infections, the expansion of the T helper cells did not plateau—they kept expanding and cleared the infection faster. Further experiments revealed that Tregs suppress the normal immune response by continuously expressing and shedding the CTLA-4 molecule, which interferes with the normal immune function of T helper cells. It also interferes with another set of T helper cells (follicular T helper cells) whose job it is to help make antibodies against malaria.

“Tregs meddle with these processes through the CTLA-4 molecule,” Dr. Harty stated.

Interestingly, blocking CTLA-4 at the right time during blood-stage infection cured mice of the infection and promoted immunity against reinfection. It even protected against a challenge from another deadlier malaria parasite.

Previous work by Dr. Harty and his team found that blocking a different checkpoint protein called programmed death-ligand 1 (PD-L1) at a later point in malaria infection also improved the host immune response to malaria. The new work shows that the CTLA-4 pathway is in play at an earlier stage in malaria infection, and shows that the two pathways don't overlap.

“Both pathways impede the appropriate activation of the immune system, but in different ways, targeting different interactions, and at different time points,” Dr. Harty remarked. “The more we understand how and when these pathways are operating, the better chance we have to rescue them.”

While the investigators were quick to point out that findings in mice often do not translate easily to human patients, they noted that access to unique human data might help determine if the CTLA-4 findings are relevant in humans.

“This has been a very potent resource for us,” Dr. Harty explained. “When we look at blood samples from the same infection timeframe that we investigated in the mouse, we see some of the same immune changes (expansion of Tregs and upregulation of CTLA-4) are also happening in humans. That does not prove that everything is the same, but at the level of resolution that we have, there is some reasonable similarity.”

“Practically, we have shown there is a pathway that can be targeted, and although CTLA-4 blockers that are available as cancer immunotherapies are too costly and impractical to use for malaria, there may be other parts of this immunological pathway that could be targeted using other drugs or small molecules, to produce the same effect,” Dr. Kurup concluded.



















