Plasmodium falciparum and the "cat-and-mouse game" of human immune cells

Reporter Feng Lifei

The relationship between pathogens and the human immune system is like a cat-and-mouse game, and "cats" need to monitor and track the trajectory of "mice" to resist pathogen invasion. In this game, cunning pathogens will use various means to blind the immune system's surveillance, and then destroy the human body, and the immune system will also "see tricks" and evolve corresponding strategies.

In a study published in the Cell Report on August 24, Gao Fu's team, an academician of the Chinese Academy of Sciences, revealed the molecular mechanism of immune escape of such a cunning "mouse", Plasmodium falciparum, and the countermeasure strategy of the host, which provided a theoretical basis for the development of antimalarial drugs and vaccine design.

Game: "Hiding the Sky and Crossing the Sea" vs."

Malaria is an insect-borne infectious disease caused by the parasite and transmitted by the bite of female Anopheles mosquitoes. Its infection is mainly manifested as clinical symptoms such as chills, fever, and anemia, which lead to death when severe, and is a disease that seriously threatens human health.

At the end of June this year, the World Health Organization (WHO) declared China a malaria-free country, which also brought the number of malaria-free countries in the world to 40. Worldwide, however, malaria continues to have a non-negligible impact on humanity. According to the WHO, there were 229 million malaria cases worldwide in 2019, with 409 000 deaths.

"Scientists have found that there are 6 species of plasmodium that can cause human disease, of which Plasmodium falciparum is the most lethal pathogenic parasite that causes falciparum malaria." Song Hao, co-corresponding author of the paper and an associate researcher at the Beijing Institute of Life Sciences of the Chinese Academy of Sciences, said in an interview with China Science Daily.

He explained that plasmodium falciparum infected with red blood cells can express a variety of proteins such as PfEMP1, STEVOR and RIFIN, like a "smokescreen bomb". The expression of these proteins on the surface of red blood cells will help the malaria parasite to "hide from the sky" and evade the host's immune surveillance.

Where there is fraud, there is anti-fraud. In recent years, scientists have isolated public antibodies from malaria patients that identify the RIFIN protein expressed on the surface of infected erythrocytes through "clues" — inserted LAIR1 extracellular segments (LAIR1Ab, all with different mutations).

"LAIR1 is an immunosuppressive receptor expressed on the surface of NK cells, T cells, and other immune cells. RiFIN protein is the largest family of variable antigens known to plasmodium falciparum, encoding 150 to 200 rif genes per malaria parasite genome. Qi Jianxun, co-corresponding author of the paper and a researcher at the Institute of Microbiology of the Chinese Academy of Sciences, said, "How do these RIFIN members combine with LAIR1? How do antibodies with LAIR1Ab fragment insertions work? These have become scientific problems that need to be solved urgently. ”

In view of these problems, Gao Fu, Song Hao, Qi Jianxun, etc. explained the interaction mechanism between PLAS Falciparum RIFIN protein and the host immunosuppressive receptor LAIR1 from the molecular level, and revealed the molecular mechanism of immune escape of Plasmodium falciparum and the countermeasure strategy of the host.

"This is the first report on the interaction between RIFIN and LAIR1 and has important implications for the field." One reviewer commented.

Invasion: "Ming Xiu Zhan Dao" + "Darkness Chen Cang"

After the malaria parasite "hides the sky and crosses the sea", how to suppress the human immune system? In the study, the authors found that the RIFIN protein not only "ming xiu zhan dao", but also "dark chen cang", through different ways combined with LAIR1 molecules, inhibiting the human immune mechanism.

By analyzing the monomer structure of RIFIN and the complex structure of the two RIFIN members and LAIR1/LAIR1Ab, the research team found that the extracellular segment of the RIFIN protein is composed of a conserved region and a variable region, which identifies LAIR1 through the variable region, and forms a similar "watchtower" structure dominated by α spiral and flexible region in the variable region, using two flexible rings at the top and a α spiral to bind to LAIR1.

This "watchtower" structure is the "boardwalk" where the RIFIN protein connects the LAIR1 molecule. "Both RIFIN members target similar binding regions on LAIR1, but the angles of binding are different, indicating that different MEMBERS of RIFIN have strong structural plasticity due to sequence diversity." Qi Jianxun said.

Interestingly, by further comparing the details of THE INTERACTION between RIFIN and LAIR1, they found that the binding sites of RIFIN and LAIR1 partially overlapped with the binding sites of LAIR1 and its native ligand collagen, indicating that RIFIN may be able to inhibit the function of immune cells by simulating the "darkness aging" of collagen and binding to LAIR1.

In addition, Song Hao said that studies have found that some RIFIN molecules can bind to another immunosuppressive receptor, LILRB1, thereby inhibiting the function of immune cells. The comparison found that RIFIN members used different binding sites to bind to LAIR1 or LILRB1, a phenomenon that further indicates the diversity of RIFIN family members.

Defeat the enemy: Enhance the "affinity" and cut off the hook

In the face of the invasion of malaria parasites, how can antibodies defeat the enemy? In the study, the authors found that the LAIR1Ab mutation inserted by the antibody had a molecular mechanism of "enhanced affinity."

Gao Fu et al. found that the RIFIN-LAIR1 interaction can cause signal activation downstream of the LAIR1 receptor, while the public antibodies with LAIR1Ab insertion, such as MGD21 and MGM5, can block the activation of the downstream signal of LAIR1 caused by RIFIN.

"This reveals that the malaria parasite uses the RIFIN protein to interact with the immunosuppressive receptor LAIR1 to achieve immune escape." Song Hao explains, "Instead, in response to malaria parasite infection, the host produces a public antibody with LAIR1Ab insertion to block the RIFIN-LAIR1 interaction." ”

Based on this, the authors revealed that Plasmodium falciparum uses the RIFIN protein on the surface of infected erythrocytes to regulate host immune cell function, elucidating the immune escape mechanism of Plasmodium falciparum, and the host immune countermeasures by generating public antibodies, indicating that plasmodium and host have produced a game mechanism based on RIFIN-LAIR1 in the long-term evolutionary process.

"This study very gracefully addresses the question of how RIFINs bind to LAIR1 and how antibodies containing LAIR1 work, which is a very good structural work." Another reviewer commented.