Evolution of virulence: coinfection and propagule production in spore-producing parasites

Background  

The evolution of within-host growth rates by parasites is expected to depend on a trade-off between propagule production and virulence. The presence of coinfections, however, is thought to alter this trade-off, and hence alter the evolutionarily stable strategy (ESS) for the parasite. Here I consider a model wherein the number of coinfections that are identical by descent can depend on the parasite's reproductive strategy. Transmission success was treated as being either a negative-linear or a negative-exponential function of the total number of propagules produced by all coinfections.     

Local host competition in the evolution of virulence

The evolution of parasite life histories should usually have correlated effects on host survivorship and/or reproductive success. For example, parasites that reproduce more rapidly might be expected to cause greater reductions in host fitness. Important theoretical advances have recently been made on virulence evolution, but the results are not always consistent. Here I compare two models [ Q. Rev. Biol. 71 (1996) 37 ; Q. Rev. Biol. 75 (2000) 261 ] on the evolution of virulence that get qualitatively different results with respect to the effects of coinfection. I also construct a third model that attempts to connect these two formulations. The results suggest that parasite growth rates should increase as local host competition increases, unless relatedness is at equilibrium. In addition, the qualitative effect of adding coinfections on parasite growth rates depends critically on how the number of coinfections affects transmission success.     

Host sexual dimorphism affects the outcome of within‐host pathogen competition

Natural infections often consist of multiple pathogens of the same or different species. When coinfections occur, pathogens compete for access to host resources and fitness is determined by how well a pathogen can reproduce compared to its competitors. Yet not all hosts provide the same resource pool. Males and females, in particular, commonly vary in both their acquisition of resources and investment in immunity, but their ability to modify any competition between different pathogens remains unknown. Using the Daphnia magna–Pasteuria ramosa model system, we exposed male and female hosts to either a single genotype infection or coinfections consisting of two pathogen genotypes of varying levels of virulence. We found that coinfections within females favored the transmission of the more virulent pathogen genotype, whereas coinfections within male hosts resulted in equal transmission of competing pathogen genotypes. This contrast became less pronounced when the least virulent pathogen was able to establish an infection first, suggesting that the influence of host sex is shaped by priority effects. We suggest that sex is a form of host heterogeneity that may influence the evolution of virulence within coinfection contexts and that one sex may be a reservoir for pathogen genetic diversity in nature.     

Host resistance and pathogen aggressiveness are key determinants of coinfection in the wild

Coinfection, whereby the same host is infected by more than one pathogen strain, may favor faster host exploitation rates as strains compete for the same limited resources. Hence, coinfection is expected to have major consequences for pathogen evolution, virulence, and epidemiology. Theory predicts genetic variation in host resistance and pathogen infectivity to play a key role in how coinfections are formed. The limited number of studies available has demonstrated coinfection to be a common phenomenon, but little is known about how coinfection varies in space, and what its determinants are. Our aim is to understand how variation in host resistance and pathogen infectivity and aggressiveness contribute to how coinfections are formed in the interaction between fungal pathogen Podosphaera plantaginis and Plantago lanceolata. Our phenotyping study reveals that more aggressive strains are more likely to form coinfections than less aggressive strains in the natural populations. In the natural populations most of the variation in coinfection is found at the individual plant level, and results from a common garden study confirm the prevalence of coinfection to vary significantly among host genotypes. These results show that genetic variation in both the host and pathogen populations are key determinants of coinfection in the wild.     

Visceral Leishmaniasis and HIV Coinfection in Latin America

Visceral leishmaniasis (VL) is an endemic zoonotic disease in Latin America caused by Leishmania (Leishmania) infantum, which is transmitted by sand flies from the genus Lutzomyia. VL occurs in 12 countries of Latin America, with 96% of cases reported in Brazil. Recently, an increase in VL, primarily affecting children and young adults, has been observed in urban areas of Latin America. The area in which this spread of VL is occurring overlaps regions with individuals living with HIV, the number of whom is estimated to be 1.4 million people by the World Health Organization. This overlap is suggested to be a leading cause of the increased number of reported VL-HIV coinfections. The clinical progression of HIV and L. infantum infections are both highly dependent on the specific immune response of an individual. Furthermore, the impact on the immune system caused by either pathogen and by VL-HIV coinfection can contribute to an accelerated progression of the diseases. Clinical presentation of VL in HIV positive patients is similar to patients without HIV, with symptoms characterized by fever, splenomegaly, and hepatomegaly, but diarrhea appears to be more common in coinfected patients. In addition, VL relapses are higher in coinfected patients, affecting 10% to 56.5% of cases and with a lethality ranging from 8.7% to 23.5% in Latin America, depending on the study. With regards to the diagnosis of VL, parasitological tests of bone marrow aspirates have proven to be the most sensitive test in HIV-infected patients. Serologic tests have demonstrated a variable sensitivity according to the method and antigens used, with the standard tests used for diagnosing VL in Latin America displaying lower sensitivity. For this review, few articles were identified that related to VL-HIV coinfections and originated from Latin America, highlighting the need for improving research within the regions most greatly affected. We strongly support the formation of a Latin American network for coinfections of Leishmania and HIV to improve the consistency of research on the current situation of VL-HIV coinfections. Such a network would improve the collection of vital data and samples for better understanding of the clinical manifestations and immunopathogenic aspects of VL in immunosuppressed patients. Ultimately, a concerted effort would improve trials for new diagnostic methodologies and therapeutics, which could accelerate the implementation of more specific and effective diagnosis as well as public policies for treatments to reduce the impact of VL-HIV coinfections on the Latin American population.     

Varicella Coinfection in Patients with Active Monkeypox in the Democratic Republic of the Congo

From 2006 to 2007, an active surveillance program for human monkeypox (MPX) in the Democratic Republic of the Congo identified 151 cases of coinfection with monkeypox virus and varicella zoster virus from 1158 suspected cases of human MPX (13%). Using clinical and socio-demographic data collected with standardized instruments by trained, local nurse supervisors, we examined a variety of hypotheses to explain the unexpectedly high proportion of coinfections among the sample, including the hypothesis that the two viruses occur independently. The probabilities of disease incidence and selection necessary to yield the observed sample proportion of coinfections under an assumption of independence are plausible given what is known and assumed about human MPX incidence. Cases of human MPX are expected to be underreported, and more coinfections are expected with improved surveillance.     

Fungal co-infection in COVID-19 patients: Should we be concerned?

Critically ill COVID-19 patients have higher pro-inflammatory (IL-1, IL-2, IL-6, tumor necrosis alpha) and anti-inflammatory (IL-4, IL-10) cytokine levels, less CD₄ interferon-gamma expression, and fewer CD₄ and CD₈ cells. This severe clinical situation increases the risk of serious fungal infections, such as invasive pulmonary aspergillosis, invasive candidiasis or Pneumocystis jirovecii pneumonia. However, few studies have investigated fungal coinfections in this population. We describe an update on published reports on fungal coinfections and our personal experience in three Spanish hospitals. We can conclude that despite the serious disease caused by SARS-CoV-2 in many patients, the scarcity of invasive mycoses is probably due to the few bronchoscopies and necropsies performed in these patients because of the high risk in aerosol generation. However, the presence of fungal markers in clinically relevant specimens, with the exception of bronchopulmonary colonization by Candida, should make it advisable to early implement antifungal therapy.     

Coinfecting parasites can modify fluctuating selection dynamics in host–parasite coevolution

Genetically specific interactions between hosts and parasites can lead to coevolutionary fluctuations in their genotype frequencies over time. Such fluctuating selection dynamics are, however, expected to occur only under specific circumstances (e.g., high fitness costs of infection to the hosts). The outcomes of host–parasite interactions are typically affected by environmental/ecological factors, which could modify coevolutionary dynamics. For instance, individual hosts are often infected with more than one parasite species and interactions between them can alter host and parasite performance. We examined the potential effects of coinfections by genetically specific (i.e., coevolving) and nonspecific (i.e., generalist) parasite species on fluctuating selection dynamics using numerical simulations. We modeled coevolution (a) when hosts are exposed to a single parasite species that must genetically match the host to infect, (b) when hosts are also exposed to a generalist parasite that increases fitness costs to the hosts, and (c) when coinfecting parasites compete for the shared host resources. Our results show that coinfections can enhance fluctuating selection dynamics when they increase fitness costs to the hosts. Under resource competition, coinfections can either enhance or suppress fluctuating selection dynamics, depending on the characteristics (i.e., fecundity, fitness costs induced to the hosts) of the interacting parasites.     

The landscape of lysogeny across microbial community density,diversity and energetics

Lysogens are common at high bacterial densities, an observation that contrasts with the prevailing view of lysogeny as a low-density refugium strategy. Here, we review the mechanisms regulating lysogeny in complex communities and show that the additive effects of coinfections, diversity and host energic status yield a bimodal distribution of lysogeny as a function of microbial densities. At high cell densities (above 10⁶ cells ml⁻¹ or g⁻¹) and low diversity, coinfections by two or more phages are frequent and excess energy availability stimulates inefficient metabolism. Both mechanisms favour phage integration and characterize the Piggyback-the-Winner dynamic. At low densities (below 10⁵ cells ml⁻¹ or g⁻¹), starvation represses lytic genes and extends the time window for lysogenic commitment, resulting in a higher frequency of coinfections that cause integration. This pattern follows the predictions of the refugium hypothesis. At intermediary densities (between 10⁵ and 10⁶ cells ml⁻¹ or g⁻¹), encounter rates and efficient energy metabolism favour lysis. This may involve Kill-the-Winner lytic dynamics and induction. Based on these three regimes, we propose a framework wherein phage integration occurs more frequently at both ends of the host density gradient, with distinct underlying molecular mechanisms (coinfections and host metabolism) dominating at each extreme.     

HIV,HBV and HCV Coinfection Prevalence in Iran - A Systematic Review and Meta-Analysis

Background

worldwide, hepatitis C and B virus infections (HCV and HCV), are the two most common coinfections with human immunodeficiency virus (HIV) and has become a major threat to the survival of HIV-infected persons. The review aimed to estimate the prevalence of HIV, HBV, HCV, HIV/HCV and HIV/HBV and triple coinfections in different subpopulations in Iran.

Method

Following PRISMA guidelines, we conducted a systematic review and meta-analysis of reports on prevalence of HIV, HBV, HCV and HIV coinfections in different subpopulations in Iran. We systematically reviewed the literature to identify eligible studies from January 1996 to March 2012 in English or Persian/Farsi databases. We extracted the prevalence of HIV antibodies (diagnosed by Elisa confirmed with Western Blot test), HCV antibodies and HBsAg (with confirmatory laboratory test) as the main primary outcome. We reported the prevalence of the three infections and coinfections as point and 95% confidence intervals.

Findings

HIV prevalence varied from %0.00 (95% CI: 0.00–0.003) in the general population to %17.25 (95% CI: 2.94–31.57) in people who inject drugs (PWID). HBV prevalence ranged from % 0.00 (95% CI: 0.00–7.87) in health care workers to % 30.9 (95% CI: 27.88–33.92) in PWID. HCV prevalence ranged from %0.19 (95% CI: 0.00–0.66) in health care workers to %51.46 (95% CI: 34.30–68.62) in PWID. The coinfection of HIV/HBV and also HIV/HCV in the general population and in health care workers was zero, while the most common coinfections were HIV/HCV (10.95%), HIV/HBV (1.88%) and triple infections (1.25%) in PWID.

Conclusions

We found that PWID are severely and disproportionately affected by HIV and the other two infections, HCV and HBV. Screenings of such coinfections need to be reinforced to prevent new infections and also reduce further transmission in their community and to others.     

Decreased overall virulence in coinfected hosts leads to the persistence of virulent parasites

Multiple infections are known to affect virulence evolution. Some studies even show that coinfections may decrease the overall virulence (the disease-induced mortality of a coinfected host). Yet, epidemiological studies tend to overlook the overall virulence, and within-host models tend to ignore epidemiological processes. Here, I develop an epidemiological model where overall virulence is an explicit function of the virulence of the coinfecting strains. I show that in most cases, a unique strain is evolutionarily stable (in accordance with the model I use here). However, when the overall virulence is lower than the virulence of each of the coinfecting strains (i.e., when coinfections decrease virulence), the evolutionary equilibrium may be invaded by highly virulent strains, leading to the coexistence of two strains on an evolutionary timescale. This model has theoretical and experimental implications: it underlines the importance of overall virulence and of epidemiological feedbacks on virulence evolution.     

Investigating disease severity in an animal model of concurrent babesiosis and Lyme disease

The incidence of babesiosis, Lyme disease and other tick-borne diseases has increased steadily in Europe and North America during the last five decades. Babesia microti is transmitted by species of Ixodes, the same ticks that transmit the Lyme disease-causing spirochete, Borrelia burgdorferi. B. microti can also be transmitted through transfusion of blood products and is the most common transfusion-transmitted infection in the U.S.A. Ixodes ticks are commonly infected with both B. microti and B. burgdorferi, and are competent vectors for transmitting them together into hosts. Few studies have examined the effects of coinfections on humans and they had somewhat contradictory results. One study linked coinfection with B. microti to a greater number of symptoms of overall disease in patients, while another report indicated that B. burgdorferi infection either did not affect babesiosis symptoms or decreased its severity. Mouse models of infection that manifest pathological effects similar to those observed in human babesiosis and Lyme disease offer a unique opportunity to thoroughly investigate the effects of coinfection on the host. Lyme disease has been studied using the susceptible C3H mouse infection model, which can also be used to examine B. microti infection to understand pathological mechanisms of human diseases, both during a single infection and during coinfections. We observed that high B. microti parasitaemia leads to low haemoglobin levels in infected mice, reflecting the anaemia observed in human babesiosis. Similar to humans, B. microti coinfection appears to enhance the severity of Lyme disease-like symptoms in mice. Coinfected mice have lower peak B. microti parasitaemia compared to mice infected with B. microti alone, which may reflect attenuation of babesiosis symptoms reported in some human coinfections. These findings suggest that B. burgdorferi coinfection attenuates parasite growth while B. microti presence exacerbates Lyme disease-like symptoms in mice.     

Interactions among symbionts operate across scales to influence parasite epidemics

Parasite epidemics may be influenced by interactions among symbionts, which can depend on past events at multiple spatial scales. Within host individuals, interactions can depend on the sequence in which symbionts infect a host, generating priority effects. Across host individuals, interactions can depend on parasite phenology. To test the roles of parasite interactions and phenology in epidemics, we embedded multiple cohorts of sentinel plants, grown from seeds with and without a vertically transmitted symbiont, into a wild host population, and tracked foliar infections caused by three common fungal parasites. Within hosts, parasite growth was influenced by coinfections, but coinfections were often prevented by priority effects among symbionts. Across hosts, parasite phenology altered host susceptibility to secondary infections, symbiont interactions and ultimately the magnitude of parasite epidemics. Together, these results indicate that parasite phenology can influence parasite epidemics by altering the sequence of infection and interactions among symbionts within host individuals.     

季节性流感病毒与其他病原混合或继发感染的研究进展与思考

流感病毒包括甲(A)、乙(B)、丙(C)和丁(D)四种型。人流行性感冒是由甲型和乙型季节性流感病毒引起的一种急性呼吸道传染病。流感病毒感染患者主要表现出呼吸道症状,严重时可以导致肺炎。此外,与其他病毒、细菌和支原体等病原体混合或继发感染时,会增加流感患者的重症率和死亡率。近几年,流感病毒与其他病原协同感染的病例有增加趋势。本文归纳总结了流感病毒与其他病原混合及继发感染的研究现状,希望为流感病毒复杂感染情况的临床诊断和治疗方案的制定提供线索。     

Social immunity modulates competition between coinfecting pathogens

Coinfections with multiple pathogens can result in complex within‐host dynamics affecting virulence and transmission. While multiple infections are intensively studied in solitary hosts, it is so far unresolved how social host interactions interfere with pathogen competition, and if this depends on coinfection diversity. We studied how the collective disease defences of ants – their social immunity – influence pathogen competition in coinfections of same or different fungal pathogen species. Social immunity reduced virulence for all pathogen combinations, but interfered with spore production only in different‐species coinfections. Here, it decreased overall pathogen sporulation success while increasing co‐sporulation on individual cadavers and maintaining a higher pathogen diversity at the community level. Mathematical modelling revealed that host sanitary care alone can modulate competitive outcomes between pathogens, giving advantage to fast‐germinating, thus less grooming‐sensitive ones. Host social interactions can hence modulate infection dynamics in coinfected group members, thereby altering pathogen communities at the host level and population level.     

On state-space reduction in multi-strain pathogen models, with an application to antigenic drift in influenza A

Many pathogens exist in phenotypically distinct strains that interact with each other through competition for hosts. General models that describe such multi-strain systems are extremely difficult to analyze because their state spaces are enormously large. Reduced models have been proposed, but so far all of them necessarily allow for coinfections and require that immunity be mediated solely by reduced infectivity, a potentially problematic assumption. Here, we suggest a new state-space reduction approach that allows immunity to be mediated by either reduced infectivity or reduced susceptibility and that can naturally be used for models with or without coinfections. Our approach utilizes the general framework of status-based models. The cornerstone of our method is the introduction of immunity variables, which describe multi-strain systems more naturally than the traditional tracking of susceptible and infected hosts. Models expressed in this way can be approximated in a natural way by a truncation method that is akin to moment closure, allowing us to sharply reduce the size of the state space, and thus to consider models with many strains in a tractable manner. Applying our method to the phenomenon of antigenic drift in influenza A, we propose a potentially general mechanism that could constrain viral evolution to a one-dimensional manifold in a two-dimensional trait space. Our framework broadens the class of multi-strain systems that can be adequately described by reduced models. It permits computational, and even analytical, investigation and thus serves as a useful tool for understanding the evolution and ecology of multi-strain pathogens.     

Evolutionary genomics of a temperate bacteriophage in an obligate intracellular bacteria (Wolbachia)

Genome evolution of bacteria is usually influenced by ecology, such that bacteria with a free-living stage have large genomes and high rates of horizontal gene transfer, while obligate intracellular bacteria have small genomes with typically low amounts of gene exchange. However, recent studies indicate that obligate intracellular species that host-switch frequently harbor agents of horizontal transfer such as mobile elements. For example, the temperate double-stranded DNA bacteriophage WO in Wolbachia persistently transfers between bacterial coinfections in the same host. Here we show that despite the phage's rampant mobility between coinfections, the prophage's genome displays features of constraint related to its intracellular niche. First, there is always at least one intact prophage WO and usually several degenerate, independently-acquired WO prophages in each Wolbachia genome. Second, while the prophage genomes are modular in composition with genes of similar function grouping together, the modules are generally not interchangeable with other unrelated phages and thus do not evolve by the Modular Theory. Third, there is an unusual core genome that strictly consists of head and baseplate genes; other gene modules are frequently deleted. Fourth, the prophage recombinases are diverse and there is no conserved integration sequence. Finally, the molecular evolutionary forces acting on prophage WO are point mutation, intragenic recombination, deletion, and purifying selection. Taken together, these analyses indicate that while lateral transfer of phage WO is pervasive between Wolbachia with occasional new gene uptake, constraints of the intracellular niche obstruct extensive mixture between WO and the global phage population. Although the Modular Theory has long been considered the paradigm of temperate bacteriophage evolution in free-living bacteria, it appears irrelevant in phages of obligate intracellular bacteria.     

Effects of malaria double infection in birds: one plus one is not two

Avian malaria parasites are supposed to exert negative effects on host fitness because these intracellular parasites affect host metabolism. Recent advances in molecular genotyping and microscopy have revealed that coinfections with multiple parasites are frequent in bird-malaria parasite systems. However, studies of the fitness consequences of such double infections are scarce and inconclusive. We tested if the infection with two malaria parasite lineages has more negative effects than single infection using 6 years of data from a natural population of house martins. Survival was negatively affected by both types of infections. We found an additive cost from single to double infection in body condition, but not in reproductive parameters (double-infected had higher reproductive success). These results demonstrate that malaria infections decrease survival, but also have different consequences on the breeding performance of single- and double-infected wild birds.     

Competition between strains of Borrelia afzelii in the host tissues and consequences for transmission to ticks

Pathogen species often consist of genetically distinct strains, which can establish mixed infections or coinfections in the host. In coinfections, interactions between pathogen strains can have important consequences for their transmission success. We used the tick-borne bacterium Borrelia afzelii, which is the most common cause of Lyme disease in Europe, as a model multi-strain pathogen to investigate the relationship between coinfection, competition between strains, and strain-specific transmission success. Mus musculus mice were infected with one or two strains of B. afzelii, strain transmission success was measured by feeding ticks on mice, and the distribution of each strain in six different mouse organs and the ticks was measured using qPCR. Coinfection and competition reduced the tissue infection prevalence of both strains and changed their bacterial abundance in some tissues. Coinfection and competition also reduced the transmission success of the B. afzelii strains from the infected hosts to feeding ticks. The ability of the B. afzelii strains to establish infection in the host tissues was strongly correlated with their transmission success to the tick vector. Our study demonstrates that coinfection and competition between pathogen strains inside the host tissues can have major consequences for their transmission success.Subject terms: Microbial ecology, Bacteria     

Prevalence of honeybee viruses in the Czech Republic and coinfections with other honeybee disease

Six bee viruses, which occur in Apis mellifera, were monitored in the Czech Republic between 2006 and 2009. Samples of larvae and pupae collected from hives where American foulbrood was detected were screened for bee viruses and in the 125 samples of larvae, there was no confirmed case of a larva infected with both American foulbrood and a bee virus. Of 145 samples infected with the protozoan Nosema apis, there were 23 cases of coinfections with the BQCV virus, 18 with the DWV virus and 11 with the ABPV virus. All coinfections with three or four viruses were also statistically significant apart from the one between ABPV with CBPV and DWV. The PCA ordination diagram indicates that BQCV occurs mainly with Nosema apis and DWV mainly with ABPV.