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Paola Marcella Camargo Minoprio: A new front against emerging diseases

The Pasteur Institute in Paris, USP, and FIOCRUZ start partnership under coordination of São Paulo biomedical scientist

"Members of the Institut Pasteur International Network are united by the desire to solve public health issues"

Léo Ramos Chaves

Seventeen research laboratories—including one at level 3 on a biosafety scale of 1 to 4—for the study of high-risk viruses now occupy an area of 1,700m2 on two floors in one of the new buildings at the São Paulo campus of the University of São Paulo (USP) in the Cidade Universitária (University Center). This is the Scientific Platform Pasteur-USP (SPPU), launched in early July, as a result of an agreement between the Pasteur Institute in Paris, USP, and Oswaldo Cruz Foundation (FIOCRUZ) from Rio de Janeiro. The creation of the Platform foresees the possible establishment of a Pasteur Institute Research Center in Brazil. The renowned French institution, which recently celebrated its 130th anniversary, is not to be confused with the São Paulo–based institute of the same name, established in 1903, which specializes in rabies virus research and is linked to the State Health Department.

With an initial budget of around R$8 million, resulting from a research project recently approved by FAPESP, the São Paulo team will work on emerging and neglected diseases, especially those that lead to impairment of the central nervous system, such as Zika virus disease, dengue fever, yellow fever, influenza, and animal sleeping sickness. “We want to act before epidemics take hold,” declares São Paulo–based biomedical technician Paola Minoprio—who, in 2014, initiated the process that led to the construction of the Platform, of which she was appointed coordinator by the Pasteur Institute. On the USP side, the supervisor is biologist Luis Carlos de Souza Ferreira, director of the Institute of Biomedical Sciences (ICB).

Minoprio’s credentials include an undergraduate degree from the University of Mogi das Cruzes, a master’s degree from USP, and a PhD from the University of Paris VI—the latter obtained while she was already working in a laboratory at the Pasteur Institute in the French capital. Upon getting hired, in 1985, Minoprio became a pasteurienne—a prestigious scientific title—and three years ago, she decided to return to São Paulo. An expert in Chagas disease, in early 2019 Minoprio packed her bags and, along with her 20-year-old dog Tico and 10-year-old cat La Samba Dora de Bourgogne, returned to São Paulo at the age of 63, drawn by the professional challenge of integrating Brazil into the international network of research centers linked to the Pasteur Institute in Paris—to which she herself remains linked. In the following interview, Minoprio elaborates on the projects to be executed in Brazil.

The first obstacle was associating a French private institution with a public university in São Paulo and a federal government foundation

How large is the Institut Pasteur International Network?
There are 33 institutes linked to the Pasteur Institute in Paris, in 25 countries, employing a total of 23,000 researchers. Generally, the Institute participates in defining scientific strategies—but not always, because each institute has its own rules and funding protocols. The Paris Institute is a private, nonprofit, public utility institution. Most of its funding—about 60%—comes from royalties from the sale of vaccines and diagnostic kits; 20% to 25% comes from donations and inheritances; and the rest comes from the French government, mainly from CNRS [National Center for Scientific Research] and INSERM [National Institute of Health and Medical Research]. The Montevideo Institute, created in 2004 because of a World War I debt owed by the French government, is now entirely maintained by the Uruguayan government, but members of the Paris Institute are members of the boards of directors and administrators. The Italy Institute kept its original name, Fondazione Cenci Bolognetti, and has always been private. China’s Institute is public, and includes the Chinese Academy of Sciences. The one in Guinea, Africa, is being built at the government’s request—after the Paris teams contributed to staff training, patient care, and field research to stop the Ebola outbreak some four years ago.

How are the different cultures of each country dealt with?
The people who work for Institut Pasteur’s International Network (RIIP) are united by their desire to solve public health issues. There is a lot of interaction. The International Directors of the Paris Institute organize annual network meetings through the Pasteur International Network Association—PINA—to discuss research and course priorities. The network is also divided by regions: Europe, America, Asia, Africa, and the Maghreb [northwestern Africa]. The America region of the network includes Canada, Guadeloupe, French Guiana, and Uruguay, where there are formalized institutes, and Brazil. There is not yet an institute linked to RIIP in Brazil, but FIOCRUZ has been a part of the network since 2004 as a corresponding institution.

What was your role in creating the Platform Pasteur-USP?
In 2000, Philippe Kourilsky—the then director-general of the Institute—assigned me to a mission: to create a research, teaching, and innovation network between the Pasteur Institute and the Mercosur academic institutions. Along with colleagues from Argentina, Uruguay, Paraguay, Brazil, and Chile, we have created a network comprised of 55 academic institutions and research centers, and 11 universities: Amsud-Pasteur. In five years, we conducted 23 regional courses, three bioenterprise excursions to Brazil, Uruguay, and Chile, and several South American students attended courses in Paris. The network was important for the creation of the Pasteur Institute of Montevideo in 2004. In 2014, the then director of the institute, Christian Bréchot, told me: “It is inevitable we will increase our collaborations with Brazil.” I sought out professor Erney Plessmann de Camargo, with whom I began my research career during my senior year internship. He advised me to speak to Marco Antonio Zago, then dean of USP and current president of FAPESP. He also suggested that I talk to Celso Lafer, then president of FAPESP, and Jorge Kalil, who was the director of the Butantan Institute. All three were interested in supporting a strategy that could lead to implementing a Pasteur Institute in Brazil.

What was the process like?
The Pasteur Institute favored the USP proposal. Zago had ceased all construction on campus, but then assigned about R$35 million to finish the building complex we now occupy. I brought engineers from the Paris Institute to work with the management of the USP Physical Space to determine the building plan and the needs of the research labs. From 2014 to 2017, I worked both in Paris and here, moving every six months in order to monitor the construction. In June 2015, a tripartite scientific cooperation agreement was signed between the Pasteur Institute, USP, and FIOCRUZ, planning the establishment of a Pasteur Institute in Brazil. The first phase of this initiative—a transitional one—calls for the creation of a platform that allows for the consolidation of scientific relations between all partners, while the second phase establishes the conditions for the creation of the Pasteur Institute of Brazil and its inclusion in RIIP. The scientific strategy was approved by the partners in 2016, taking into account that Brazil is one of the largest biodiversity centers in the world, that chronic diseases are advancing due to aging, and that climate and environmental changes favor vector migration and the emergence of new viruses and diseases. In April 2017, the first administrative office of the Pasteur Institute in Brazil opened its doors in the Aucani [USP Agency for National and International Academic Cooperation] building. Through that office, as a manager, I can negotiate with any academic or research institution, as well as national and international official bodies. In July 2017, a new agreement created the first physical space for the Scientific Platform Pasteur-USP, the SPPU. In early July of this year, before the inauguration of the SPPU, we brought together researchers from the America region of the International Network, from the Pasteur Institute of Senegal, and from other countries in the region—such as Argentina, Chile, Peru, Bolivia, and Costa Rica. We organized a symposium on arboviruses and antibiotic resistance; we also discussed common initiatives, and, on the last day, we gathered to see how we could work together. The directors and scientists from the Pasteur Institute met with directors and scientists from other institutions.

What do you intend to do here?
A multisite strategy is being followed to establish the Pasteur Institute of Brazil. In São Paulo, the SPPU will focus its efforts on part of the scientific strategy, particularly the one that handles emerging and neglected diseases that lead to impairment of the central nervous system, such as Zika virus disease, dengue fever, yellow fever, influenza, and animal sleeping sickness. We thought about the possibility of creating another research center in Eusébio, Ceará, with FIOCRUZ; if it works, we will be close to the Pasteur Institute of French Guiana, where we have implemented a vectopôle—a center for the study of the migration patterns of insect vectors of disease-causing agents. We want to act before epidemics reach Brazil, as an emergency intervention unit. During the Zika virus epidemic, the best scientists and doctors in the field of infectiology in Brazil created a network, with support from FAPESP. With our knowledge of genomics and vector migration, we can predict the movement of new viruses and study their relationships with the body before the epidemic arrives. The July meeting was also important in order to bring together certain Brazilian groups, such as the Evandro Chagas Institute and FIOCRUZ, which will be part of this project.

Personal archives Minoprio (second row, right) with the staff of her Pasteur Institute laboratory in ParisPersonal archives

Who is part of the team?
The specialized researchers initially featured in the SPPU are: in neurobiology, Patrícia Beltrão Braga; in the field of viral diagnosis, Edison Durigon; Paolo Zanotto as a specialist in arbovirus phylogeny; in immunopathology, Jean Pierre Peron; and myself, with a specialization in the interaction between pathogens and hosts. We will try to modify the genes that will turn into the Zika virus and other colored or luminescent microorganisms, in order to see how they spread and cause inflammation in animal models. Helder Nakaya, a systems biologist, will handle big data and analyze immunological, genomic, and epidemiological data. We will also work with Eduardo Massad, an expert in mathematical models and tropical epidemiology. Pedro Teixeira da Silva, who was biosafety coordinator at the National School of Public Health (FIOCRUZ), spent a year at the Paris Institute to learn more about biosafety in level 3 laboratories, and is now here at the Platform to pass on standards of good practice, which will help us standardize research work in Brazil in relation to how it is done abroad. I am still linked to the Paris Institute, but I’ve been able to negotiate my work there down to three to four trips a year. I have finished my scientific work in Paris; my last student defended his PhD thesis last December. My laboratory still belongs to a department in the Institute called Global Health, but as the Platform’s coordinator, I can’t be in both places at the same time. I brought over most of my lab equipment in a 40m3 container, in order to adapt it for multiple users. It arrived in May and should be operational in September, along with other SPPU acquisitions funded by FAPESP.

What obstacles did you face in setting up the Platform?
The first was associating a foreign, private, public utility institution with a public, autonomous university belonging to the state of São Paulo and a foundation linked to the Ministry of Health. As they are institutions with different administrative regimes, we do not yet know whether the future Pasteur Institute of Brazil will be a subsidiary of the Paris Institute, a foundation, or an OSCIP [Civil Society Organization of Public Interest]. Another issue is putting teams together. Our goal is not to just randomly incorporate researchers, but to recognize a relevant scientific problem, identify who in Brazil or abroad is most likely to solve it, and work together.

What is your work with Chagas disease?
Based on a different strategy than that of other researchers, who were primarily interested in immunodominant antigenic determinants for pathogenic microorganisms, I directed my attention to the immune system as a whole, with specific and nonspecific responses against the offending agent. My PhD advisor was Portuguese immunologist Antonio Coutinho, who said: “The immune system was not designed to protect us from anything, but to ‘know’ and ‘recognize’ us. Everything that is not you is strange, and the body tries to either incorporate it, to find balance, or eliminate it.” During my PhD, instead of analyzing the parasite-specific response, like most parasitologists, I examined the whole immune system in the presence of a strange element—Trypanosoma cruzi, which causes Chagas disease. I found that less than 2% of a host’s immune response against an organism is specific. I saw that the parasites activate an indiscriminate, mostly nonspecific response by stimulating the production of low affinity antibodies against pathogenic microorganisms. In 2000, I discovered that T. cruzi, as it enters the body, produces the enzyme proline racemase, which stimulates significant production of nonspecific antibodies by B lymphocytes. Thus, it disturbs the whole immune system and integrates into the host. Seven to ten days after infection, the specific antiparasitic response happens, leading to the death of most parasites—but those already within the tissues remain. In 2001, I was able to show, along with my team, that injecting proline racemase prevented the turmoil caused by the parasite and induced a protection rate of 90–95%. These findings had a positive repercussion, but they were disappointing to me.

The 5% remaining parasites continue to multiply and the disease progresses. So the protection is not sterilizing. Later, in association with colleagues in the fields of molecular dynamics, crystallography, medical chemistry, and in silico modeling for drug development, we’ve been able to identify proline racemase inhibitors. I was granted funding from the  National Research Association (ANR) to develop inhibitors up to phase I. These compounds are also inhibitors for the proline racemase from Clostridium difficile bacteria, which cause difficult-to-treat infections. I finished my work on this phase in Paris, but I hope to move forward with my colleagues from France and Brazil. Now I will turn my attention toward another trypanosoma, T. vivax, which causes animal sleeping sickness, and toward emerging viruses—the main theme of SPPU.

Why did you decide to return to São Paulo for good?
Three years ago, I had to decide if I was going to stay there, based in Paris, or continue to come and go between São Paulo and Paris. In addition to the fact that my mother is 89 years old, there was the career challenge. I have been working with Chagas disease for over 30 years in Paris. How could I finish my career in France? I did nothing for my country, because I left Brazil when I was very young. No one believed that this platform would happen—but I will be happy if, in a few years when I retire, I see the young people we are educating now working here in Brazil on important things that impact public and global health.