238 Jean-Paul Gonzalez et al. pathological states present in a given population at a given time. The frequency and the distribution of each disease depend not only on endogenous—infectivity, virulence, route of infection, vector—and ecological factors—climate, urbanization, promiscuity—but also on frequency and distribution of all the other diseases within the same pop- ulation’’ (Grmek, 1969). Thus, for the ﬁrst time in the history of medicine—beyond a nosological framework that encloses diseases in a frozen disciplinary framework (e.g., respiratory diseases, arboviral diseases, sexually transmitted diseases)—Grmek offered a temporal and spatial approach to understand the dynamics of infectious diseases and their interdependency. Grmek (1969, 1997) saw the health state of a population as a complex dynamic phenomenon leading to a wide range of epidemiological patterns subject to environmental and human factors. Based on this concept of ‘‘pathocenosis,’’ Grmek examined the historical progression of diseases across Europe during the past two millennia: over time, plague succeeded leprosy and was successively followed by syphilis, smallpox, cholera, tuberculosis, and, most recently, the acquired immune deﬁciency syndrome (AIDS). Even if such a succession can be coincidental, or if appearance and disappearance of successive diseases may have the same causes, these observations raise the question of interactive causalities. Following Mirko Grmek, we propose to revisit some changes in pathocenosis in the light of the complex and dynamic processes in which the infectious agents poten- tially interact, keeping in mind the importance of the ‘‘asymptomatic infections’’ highlighted by Charles Nicolle. centuries. The massive human population declines due to plague epidemics (estimated at about 40% during the Black Death of 1347–1352 and 20% during the Great Plague of 1665–1666), from which Europe recovered only four cen- turies later, may be one cause of leprosy’s decline. The social consequences of the Plague affected the fundamental modes of transmission, as well as the distribution, of other patho- gens associated with human population density (Weiss and McMichael, 2004). Thus, the Black Death probably induced strong competition for contemporary circulating pathogens, such as the smallpox and measles viruses, which are likely to have provoked outbreaks before the arrival of the bacterium Yersinia pestis and were only able to reemerge in the 18th century (Barquet and Domingo, 1997; Hopkins, 2002) once the Plague had vanished from Europe. The European Plague (1345–1750) also appears to have exerted major genetic selective pressure, maybe explaining the high frequency of the CCR5-D32 deletion (10%), a protective allele, in the European population (Galvani and Slatkin, 2003; Duncan et al., 2005). This selection would constitute a major legacy of the Black Death and its resurgences, modulating the current pathocenosis by protecting against AIDS, for example. Fi- nally, plague is a typical example of the strong interaction between human and animal pathocenoses. Indeed, human plague outbreaks interact with pathogens of the black rat, Rattus rattus, the carrier of Y. pestis. Serious plague outbreaks are usually preceded by highly lethal disease outbreaks in reservoir rodents, from plague or other diseases, which favor transmission of infected ﬂeas to humans (Keeling and Gil- ligan, 2000; Duplantier et al., 2005; Lowell et al., 2009). CONCEPT OF PATHOCENOSIS IN THE LIGHT OF THE HISTORY OF PLAGUE IN EUROPE DEFINING INTERACTIONS BETWEEN DISEASES AND INFECTIOUS AGENTS Revisiting disease history in the light of the pathocenotic concept, i.e., taking account not only of the environmental and social contexts but also of the presence of other dis- eases or infections in the host population, provides new explanations for observed sequences of events. The history of plague pandemics illustrates several aspects of disease interdependency, not only through the direct effects of the illness but also through the legacy of plague on the host population several centuries later (certain precautions must of course be taken, as medical knowledge was poor and unreliable at the time of the epidemics). Historically, the Black Death followed on the heels of the peak in endemic leprosy, situated between the 12th and 14th Coinfection by more than one pathogen seems to be more common than infection by a single pathogen (Cox, 2001) and appears to affect the immune response to these agents (Graham et al., 2007). Cellular immune effectors (e.g., T helper 1, T helper 2, T helper 17, and cytokines) show complex mutual regulation, and this may affect the im- mune response to a second infectious agent. Witness the deleterious impact of nematode infestation on host immunity to infectious diseases such as malaria (Druilhe et al., 2005), hepatitis B and C (Kamal and Khalifa, 2006; Edwards et al., 2005) and AIDS, and even on the effectiveness of some vaccines (Su et al., 2006). Direct interactions between parasites have also been documented.