Immune-mediated Interactions Research Articles

A Drosophila melanogaster model shows that fast growing Metarhizium species are the deadliest despite eliciting a strong immune response

ABSTRACT We used Drosophila melanogaster to investigate how differences between Metarhizium species in growth rate and mechanisms of pathogenesis influence the outcome of infection. We found that the most rapid germinators and growers in vitro and on fly cuticle were the fastest killers, suggesting that pre-penetration competence is key to Metarhizium success. Virulent strains also induced the largest immune response, which did not depend on profuse growth within hosts as virulent toxin-producing strains only proliferated post-mortem while slow-killing strains that were specialized to other insects grew profusely pre-mortem. Metarhizium strains have apparently evolved resistance to widely distributed defenses such as the defensin Toll product drosomycin, but they were inhibited by Bomanins only found in Drosophila spp. Disrupting a gene (Dif), that mediates Toll immunity has little impact on the lethality of most Metarhizium strains (an exception being the early diverged M. frigidum and another insect pathogen Beauveria bassiana). However, disrupting the sensor of fungal proteases (Persephone) allowed rapid proliferation of strains within hosts (with the exception of M. album), and flies succumbed rapidly. Persephone also mediates gender differences in immune responses that determine whether male or female flies die sooner. We conclude that some strain differences in growth within hosts depend on immune-mediated interactions but intrinsic differences in pathogenic mechanisms are more important. Thus, Drosophila varies greatly in tolerance to different Metarhizium strains, in part because some of them produce toxins. Our results further develop D. melanogaster as a tractable model system for understanding insect-Metarhizium interactions.

Gut Brain axis: The gut microbiome in peri-operative medicine.

Sir, The human body is inhabited by a multitude of bacteria, viruses, fungi, phages constituting the microbiota, and their gene pool called the microbiome which is essential for human well-being.[1] The role of gut microbiome in peri-operative medicine is recently being explored. However, most of the literature available is that of animal studies and more extensive research would be needed in humans to establish an association. The mechanism of action of gut-microbiome on various systems of the human body can be explained by the “gut-brain axis.” This is a two-way interaction between the enteric nervous system (ENS) and central nervous system (CNS) [Figure 1]. The gut microbiota secrete various metabolites and products like-short chain fatty acids (SCFA), enzymes, polysaccharides, cytokines, and neurotransmitters, which are released in to the circulation to act on the CNS. The vagus nerve also carries inputs from ENS to CNS. The brain in-turn acts on the gut through the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system.[2] Immune mediated interaction and alteration of microglial activity are other proposed mechanisms of gut-brain interaction. All these mechanisms have been proven only by preclinical animal studies.[1]Figure 1: Gut brain axis. HPA = Hypothalamic pituitary adrenal axisAnaesthetic agents-like propofol and volatile anaesthetics have been found to alter the gut microbiota composition in animal studies. Han et al. studied gut microbiota of mice after sevoflurane exposure and found that microbiome composition was reduced on day-1, 3, 7, and 14 after sevoflurane anaesthesia compared to the control group. They also noted a significant difference in fecal metabolites of the experimental and control groups.[3] Also an infusion of propofol for 3 hours in rats was found to decrease the number of certain bacterial species for 14 days.[4] Postoperative delirium (POD) and post-surgical pain (PSP) have also been attributed to the gut-microbiome by animal studies. This means, why certain patients have more POD or PSP than others can be determined by their gut-microbiome constitution and may be pre-treatment with pre-biotics, post-biotics, or fecal microbiota transplantation reduces the risk of POD and PSP in these patients. However, this association between POD/PSP and gut-microbiome has been shown mostly in animal studies and human association is yet to be established.[1] Zhang et al. compared the gut-microbiota of rats who developed POD and those who did not develop POD after abdominal surgery. The composition of microbiota was significantly different between the groups. They also conducted fecal microbiota transplantation from rats with POD to antibiotic treated rats, which then developed POD.[5] A human study has proved association of gut microbiome with chronic PSP, where Yao et al. had preoperatively collected gut-microbiome samples for 132 patients undergoing breast cancer surgery. The gut microbiota of 66 patients who developed chronic PSP (CPSP) was significantly different from those who did not develop PSP. Fecal microbiome transplantation from CPSP patients to mice led to development of hyperalgesia in these mice.[6] The gut microbiome composition has been attributed to development of opioid tolerance. Chronic opioid exposure leads to activation of opioid receptors on gut epithelium and destruction of gut mucosal barrier, allowing translocation of gut bacteria leading to an inflammatory response and pain exacerbation.[1] The gut microbiota composition influences many chronic pain conditions like fibromyalgia, headache, neuropathic, visceral, and chronic pelvic pain. The mediators of gut microbiota can alter the neuronal excitability at the dorsal root ganglia and mediate neuro inflammation leading to central sensitization and peripheral sensitization in chronic pain. Thus, targeting the gut-microbiota seems to be a promising treatment of chronic pain.[1,2] In future, gut microbiome analysis might help to screen patients at risk of postoperative cognitive dysfunction, postoperative pain, chronic pain and opioid tolerance and alteration of gut microbiota by use of prebiotics, postbiotics, dietary, and life-style changes might provide therapeutic benefit in such patients. However, this hypothesis is based majorly on animal studies and gut microbiome still needs to be explored in humans. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

The Enemy of my Enemy is my Friend: Immune-Mediated Facilitation Contributes to Fitness of Co-Infecting Helminths.

The conceptual understanding of immune-mediated interactions between parasites is rooted in the theory of community ecology. One of the limitations of this approach is that most of the theory and empirical evidence has focused on resource or immune-mediated competition between parasites and yet there is ample evidence of positive interactions that could be generated by immune-mediated facilitation. We developed an immuno-epidemiological model and applied it to longitudinal data of two gastrointestinal helminths in two rabbit populations to investigate, through model testing, how immune-mediated mechanisms of parasite regulation could explain the higher intensities of both helminths in rabbits with dual than single infections. The model framework was selected and calibrated on rabbit population A and then validated on the nearby rabbit population B to confirm the consistency of the findings and the generality of the mechanisms. Simulations suggested that the higher intensities in rabbits with dual infections could be explained by a weakened or low species-specific IgA response and an asymmetrical IgA cross-reaction. Simulations also indicated that rabbits with dual infections shed more free-living stages that survived for longer in the environment, implying greater transmission than stages from hosts with single infections. Temperature and humidity selectively affected the free-living stages of the two helminths. These patterns were comparable in the two rabbit populations and support the hypothesis that immune-mediated facilitation can contribute to greater parasite fitness and local persistence.

Circulating IL-6, IL-10, and TNF-alpha and IL-10/IL-6 and IL-10/TNF-alpha ratio profiles of polyparasitized individuals in rural and urban areas of gabon

Malaria, blood-borne filarial worms and intestinal parasites are all endemic in Gabon. This geographical co-distribution leads to polyparasitism and, consequently, the possibility of immune-mediated interactions among different parasite species. Intestinal protozoa and helminths could modulate antimalarial immunity, for example, thereby potentially increasing or reducing susceptibility to malaria. The aim of the study was to compare the cytokine levels and cytokine ratios according to parasitic profiles of the population to determine the potential role of co-endemic parasites in the malaria susceptibility of populations. Blood and stool samples were collected during cross-sectional surveys in five provinces of Gabon. Parasitological diagnosis was performed to detect plasmodial parasites, Loa loa, Mansonella perstans, intestinal helminths (STHs) and protozoan parasites. Nested PCR was used to detect submicroscopic plasmodial infection in individuals with negative blood smears. A cytometric bead array was used to quantify interleukin (IL)-6, IL-10 and tumour necrosis factor (TNF)-α in the plasma of subjects with different parasitological profiles. Median IL-6 and IL-10 levels and the median IL-10/TNF-α ratio were all significantly higher among individuals with Plasmodium (P.) falciparum infection than among other participants (p<0.0001). The median TNF-α level and IL-10/IL-6 ratio were higher in subjects with STHs (p = 0.09) and P. falciparum-intestinal protozoa co-infection (p = 0.04), respectively. IL-6 (r = -0.37; P<0.01) and IL-10 (r = -0.37; P<0.01) levels and the IL-10/TNF-α ratio (r = -0.36; P<0.01) correlated negatively with age. Among children under five years old, the IL-10/TNF-α and IL-10/IL-6 ratios were higher in those with intestinal protozoan infections than in uninfected children. The IL-10/TNF-α ratio was also higher in children aged 5-15 years and in adults harbouring blood-borne filariae than in their control counterparts, whereas the IL-10/IL-6 ratio was lower in those aged 5-15 years with filariae and intestinal parasites but higher in adults with intestinal parasitic infections. Asymptomatic malaria is associated with a strong polarization towards a regulatory immune response, presenting high circulating levels of IL-10. P. falciparum/intestinal protozoa co-infections were associated with an enhanced IL-10 response. Immunity against malaria could differ according to age and carriage of other parasites. Helminths and intestinal protozoa can play a role in the high susceptibility to malaria currently observed in some areas of Gabon, but further investigations are necessary.

Abstract 10610: Schistosomiasis and Cardiovascular Disease in 1,000 HIV-Infected and Uninfected Tanzanian Adults: A Prospective Cohort Study

Background: Variations in immune phenotype are increasingly recognized as drivers of cardiovascular disease (CVD). For example, the inflammatory effect of HIV-infection is associated with a 2-fold higher risk of CVD. Conversely, schistosome infection induces an anti-inflammatory immune response, which may counter CVD pathways related to inflammation. Whether the immune regulatory effect of schistosome infection is sufficient to suppress the contrasting stimulatory effect of another disease such as HIV remains unknown and may provide critical insight into the immunologic basis of non-communicable diseases. Methods: In this prospective cohort study, we enrolled 1,000 HIV-infected and uninfected adults at a referral HIV clinic in a schistosome endemic area in Mwanza, Tanzania. Standardized history, echocardiography and serum were obtained. Blood pressure was monitored over two years. Regression models adjusted for age and sex were used to quantify associations. Results: We enrolled 503 schistosome infected and 497 uninfected adults with a median age of 36 [28- 43]. Schistosome infection was significantly associated with a lower prevalence of hypertension (39.6% vs 46.7%, p=0.016), myocardial diastolic dysfunction (8.1% vs 13.4%, p=0.015) and total-to-high density lipoprotein ratio (1.77 vs 1.82, p&lt;0.0001) as compared to uninfected participants. Additionally, schistosome-infection was associated with significantly improved change in blood pressure over time (0.67 vs 3.35 mmHg increase, p=0.005). When stratified by concurrent HIV-infection, schistosome infection was associated with lower prevalence of diastolic dysfunction and total-to-HDL ratio in HIV- infected adults but lower prevalence of hypertension in those without HIV-infection. Conclusions: We provide the first evidence that schistosome infection may directly impact cardiac function and slow the age-related increase in blood pressure over time. Further, associations between schistosome and CVD differ by HIV status, implying that immune mediated interactions may have important physiologic ramifications for CVD. The patterns of these interactions may provide insight into the immunologic mechanisms of cardiovascular diseases.

Interactions between seasonal human coronaviruses and implications for the SARS-CoV-2 pandemic: A retrospective study in Stockholm, Sweden, 2009-2020.

ObjectivesThe four seasonal coronaviruses 229E, NL63, OC43, and HKU1 are frequent causes of respiratory infections and show annual and seasonal variation. Increased understanding about these patterns could be informative about the epidemiology of SARS-CoV-2.MethodsResults from PCR diagnostics for the seasonal coronaviruses, and other respiratory viruses, were obtained for 55,190 clinical samples analyzed at the Karolinska University Hospital, Stockholm, Sweden, between 14 September 2009 and 2 April 2020.ResultsSeasonal coronaviruses were detected in 2130 samples (3.9 %) and constituted 8.1 % of all virus detections. OC43 was most commonly detected (28.4 % of detections), followed by NL63 (24.0 %), HKU1 (17.6 %), and 229E (15.3 %). The overall fraction of positive samples was similar between seasons, but at species level there were distinct biennial alternating peak seasons for the Alphacoronaviruses, 229E and NL63, and the Betacoronaviruses, OC43 and HKU1, respectively. The Betacoronaviruses peaked earlier in the winter season (Dec-Jan) than the Alphacoronaviruses (Feb-Mar). Coronaviruses were detected across all ages, but diagnostics were more frequently requested for paediatric patients than adults and the elderly. OC43 and 229E incidence was relatively constant across age strata, while that of NL63 and HKU1 decreased with age.ConclusionsBoth the Alphacoronaviruses and Betacoronaviruses showed alternating biennial winter incidence peaks, which suggests some type of immune mediated interaction. Symptomatic reinfections in adults and the elderly appear relatively common. Both findings may be of relevance for the epidemiology of SARS-CoV-2.

Abstract 1881: Immune mediated interaction between radiation and cetuximab in a syngeneic murine model of head and neck squamous cell carcinoma

Abstract Purpose: Patients with head and neck squamous cell carcinoma (HNSCC) treated with anti-EGFR (cetuximab) mAb-based immunotherapy often acquire therapy-resistance, reducing clinical benefit. We evaluated the efficacy of a combined modality in situ vaccination regimen aimed at overcoming resistance to cetuximab using a syngeneic tumor model. Experimental Design: The murine HNSCC cell line MOC2 was transduced to express human EGFR (MOC2-huEGFR) and used as a syngeneic model of therapeutic resistance to cetuximab. The cells were tested for viability, radiosensitivity, and huEGFR-specific mAb binding efficacy in the presence of cetuximab. Antibody-dependent cellular cytotoxicity (ADCC) was tested by coculture of 51chromium-labeld MOC2-huEGFR with PBMC. Mice bearing these syngeneic tumors were treated with therapeutic regimens that included local radiation (RT), intratumoral (IT) cetuximab, and/or systemic immune checkpoint inhibitors, and tumor growth/survival rate were monitored. Result: Cetuximab induced antibody-dependent cellular cytotoxicity (ADCC) in MOC2-huEGFR and PBMC co-cultures, but showed no effect on cell proliferation or radiosensitivity. Combined RT and IT-cetuximab treatment induced tumor growth delay, which required huEGFR expression, NK cells, and FcγR expression. In addition, combined RT+IT-cetuximab therapy greatly induced tumor infiltration by both CD8 T cells and NK cells. RT promoted NK cell-mediated ADCC effects against 51chromium-labeld MOC2-huEGFR with increased IFNγ expression. Proliferating tumor cells gradually increased Pd-l1 mRNA expression, and RT enhanced cell surface PD-L1 in MOC2-huEGFR cells. Systemic anti-PD-L1 antibody or IT-cetuximab alone did not show antitumor response against MOC2-huEGFR bearing mice; however, significant tumor growth inhibition was observed with combined anti-PD-L1, RT, and IT-cetuximab. Conclusion: The MOC2-huEGFR HNSCC tumor model is immunologically “cold” and does not respond to either cetuximab or anti-PD-L1 therapies alone. In this model, we show that a combination of RT+cetuximab+anti-PD-L1 elicits a cooperative in situ vaccine effect. Combining RT, cetuximab and immune checkpoint blockade may enable anti-tumor immune response in HNSCC patients with immunologically cold, huEGFR-expressing tumors. Citation Format: Wonjong Jin, Amy K. Erbe, Ciara Schwarz, Abigail Jaquish, Bryce R. Anderson, Raghava N. Sriramaneni, Justin C. Jagodinsky, Paul A. Clark, Zachary S. Morris. Immune mediated interaction between radiation and cetuximab in a syngeneic murine model of head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1881.

Life course exposures continually shape antibody profiles and risk of seroconversion to influenza.

Complex exposure histories and immune mediated interactions between influenza strains contribute to the life course of human immunity to influenza. Antibody profiles can be generated by characterizing immune responses to multiple antigenically variant strains, but how these profiles vary across individuals and determine future responses is unclear. We used hemagglutination inhibition titers from 21 H3N2 strains to construct 777 paired antibody profiles from people aged 2 to 86, and developed novel metrics to capture features of these profiles. Total antibody titer per potential influenza exposure increases in early life, then decreases in middle age. Increased titers to one or more strains were seen in 97.8% of participants during a roughly four-year interval, suggesting widespread influenza exposure. While titer changes were seen to all strains, recently circulating strains exhibited the greatest titer rise. Higher pre-existing, homologous titers at baseline reduced the risk of seroconversion to recent strains. After adjusting for homologous titer, we also found an increased frequency of seroconversion against recent strains among those with higher immunity to older previously exposed strains. Including immunity to previously exposures also improved the deviance explained by the models. Our results suggest that a comprehensive quantitative description of immunity encompassing past exposures could lead to improved correlates of risk of influenza infection.

Temporal expression of cytokines and B-cell phenotypes during mechanical circulatory support

BackgroundAllosensitization during mechanical circulatory support (MCS) is a well-described phenomenon, although its mechanism remains unknown. Although immune-mediated interactions from devices or blood transfusions have been proposed, the role of inflammation in this development is less clear. This study was undertaken to further investigate the temporal association of cytokines and B-cell phenotypes in the MCS population. MethodsAdult patients who received the Heartmate II (Thoratec, Pleasanton, Calif) at our center between September 2012 and March 2015 were prospectively followed after device implantation. Blood draws for anti-human leukocyte antigen (HLA) antibody, cytokine expression, and B-cell immunophenotyping were performed before implantation and for 3 weeks postoperatively. Time courses for cytokines and B-cell subsets were expressed using visual representations of median levels as heat maps, and mixed modeling analysis was used to model changes with time and patient factors. ResultsTwenty patients who received the Heartmate II (Thoratec) were analyzed during the study period. Four patients showed measureable levels of anti-HLA antibody during the follow-up period, although 3 of these had evidence of antibodies preoperatively. Analysis of cytokine trends revealed early (interleukin [IL]-6, IL-8, and IL-10) and late peaking (IL-3, IL-4, fibroblast growth factor 2, and CD40L) patterns. Upregulation of switched memory, transitional, and plasma blast B cells occurred over time. Right ventricular assist device use and low Interagency Registry for Mechanically Assisted Circulatory Support score were associated with decreased mature naive and increased antibody-secreting cells. ConclusionsMCS device implantation was associated with increased inflammatory cytokines and maturation of B-cell phenotypes. No patients developed de novo HLA antibodies, whereas several showed increases in anti-HLA antibody levels detected before implantation. This suggests that inflammation and maturation of existing sensitized B cells might play an important role in the pathogenesis of allosensitization in MCS.

Cross-immunity between strains explains the dynamical pattern of paramyxoviruses

Viral respiratory tract diseases pose serious public health problems. Our ability to predict and thus, be able to prepare for outbreaks is strained by the complex factors driving the prevalence and severity of these diseases. The abundance of diseases and transmission dynamics of strains are not only affected by external factors, such as weather, but also driven by interactions among viruses mediated by human behavior and immunity. To untangle the complex out-of-phase annual and biennial pattern of three common paramyxoviruses, Respiratory Syncytial Virus (RSV), Human Parainfluenza Virus (HPIV), and Human Metapneumovirus (hMPV), we adopt a theoretical approach that integrates ecological and immunological mechanisms of disease interactions. By estimating parameters from multiyear time series of laboratory-confirmed cases from the intermountain west region of the United States and using statistical inference, we show that models of immune-mediated interactions better explain the data than those based on ecological competition by convalescence. The strength of cross-protective immunity among viruses is correlated with their genetic distance in the phylogenetic tree of the paramyxovirus family.

Maternal endocrine and immune mediated interactions in placental 11β-HSD2 regulation: A role for developmental programming

Maternal endocrine and immune mediated interactions in placental 11β-HSD2 regulation: A role for developmental programming

Interactions between Micro- and Macroparasites Predict Microparasite Species Richness across Primates

Most wild animals face concurrent challenges by multiple infectious organisms, and immunological responses triggered by some parasites may increase susceptibility to other infectious agents. Immune-mediated interactions among parasites have been investigated among individuals in a population, but less is known about broader comparative patterns. We investigated the "macro-micro facilitation hypothesis" that higher helminth prevalence in a host species provides greater opportunities for intracellular parasites to invade, resulting in higher richness of intracellular microparasites. We obtained data on average helminth prevalence for 70 primate hosts, along with data on richness of intra- and extracellular infectious organisms. Using Bayesian phylogenetic methods, we found that primate species with higher overall helminth prevalence harbored more species of intracellular microparasites, while the positive association between helminth prevalence and extracellular microparasite species richness was weaker. The relationships held after controlling for potentially confounding variables, but associations were not found in focused tests of prevalence for six genera of well-studied helminths. The magnitude of support and effect sizes for overall helminth prevalence on intracellular microparasite species richness was similar to support for other well recognized ecological and life-history drivers of parasite species richness. Our findings therefore suggest that intrahost parasite interactions are as important as some ecological characteristics of hosts in accounting for parasite richness across host species.

Time and dose-dependent risk of pneumococcal pneumonia following influenza: a model for within-host interaction between influenza andStreptococcus pneumoniae

A significant fraction of seasonal and in particular pandemic influenza deaths are attributed to secondary bacterial infections. In animal models, influenza virus predisposes hosts to severe infection with both Streptococcus pneumoniae and Staphylococcus aureus. Despite its importance, the mechanistic nature of the interaction between influenza and pneumococci, its dependence on the timing and sequence of infections as well as the clinical and epidemiological consequences remain unclear. We explore an immune-mediated model of the viral-bacterial interaction that quantifies the timing and the intensity of the interaction. Taking advantage of the wealth of knowledge gained from animal models, and the quantitative understanding of the kinetics of pathogen-specific immunological dynamics, we formulate a mathematical model for immune-mediated interaction between influenza virus and S. pneumoniae in the lungs. We use the model to examine the pathogenic effect of inoculum size and timing of pneumococcal invasion relative to influenza infection, as well as the efficacy of antivirals in preventing severe pneumococcal disease. We find that our model is able to capture the key features of the interaction observed in animal experiments. The model predicts that introduction of pneumococcal bacteria during a 4-6 day window following influenza infection results in invasive pneumonia at significantly lower inoculum size than in hosts not infected with influenza. Furthermore, we find that antiviral treatment administered later than 4 days after influenza infection was not able to prevent invasive pneumococcal disease. This work provides a quantitative framework to study interactions between influenza and pneumococci and has the potential to accurately quantify the interactions. Such quantitative understanding can form a basis for effective clinical care, public health policies and pandemic preparedness.

Generating super-shedders: co-infection increases bacterial load and egg production of a gastrointestinal helminth

Co-infection by multiple parasites is common within individuals. Interactions between co-infecting parasites include resource competition, direct competition and immune-mediated interactions and each are likely to alter the dynamics of single parasites. We posit that co-infection is a driver of variation in parasite establishment and growth, ultimately altering the production of parasite transmission stages. To test this hypothesis, three different treatment groups of laboratory mice were infected with the gastrointestinal helminth Heligmosomoides polygyrus, the respiratory bacterial pathogen Bordetella bronchiseptica lux+ or co-infected with both parasites. To follow co-infection simultaneously, self-bioluminescent bacteria were used to quantify infection in vivo and in real-time, while helminth egg production was monitored in real-time using faecal samples. Co-infection resulted in high bacterial loads early in the infection (within the first 5 days) that could cause host mortality. Co-infection also produced helminth ‘super-shedders’; individuals that chronically shed the helminth eggs in larger than average numbers. Our study shows that co-infection may be one of the underlying mechanisms for the often-observed high variance in parasite load and shedding rates, and should thus be taken into consideration for disease management and control. Further, using self-bioluminescent bacterial reporters allowed quantification of the progression of infection within the whole animal of the same individuals at a fine temporal scale (daily) and significantly reduced the number of animals used (by 85%) compared with experiments that do not use in vivo techniques. Thus, we present bioluminescent imaging as a novel, non-invasive tool offering great potential to be taken forward into other applications of infectious disease ecology.

Hidden Consequences of Living in a Wormy World: Nematode‐Induced Immune Suppression Facilitates Tuberculosis Invasion in African Buffalo

Most hosts are infected with multiple parasites, and responses of the immune system to co-occurring parasites may influence disease spread. Helminth infection can bias the host immune response toward a T-helper type 2 (Th2) over a type 1 (Th1) response, impairing the host’s ability to control concurrent intracellular microparasite infections and potentially modifying disease dynamics. In humans, immune-mediated interactions between helminths and microparasites can alter host susceptibility to diseases such as HIV, tuberculosis (TB), and malaria. However, the extent to which similar processes operate in natural animal populations and influence disease spread remains unknown. We used cross-sectional, experimental, and genetic studies to show that gastrointestinal nematode infection alters immunity to intracellular microparasites in free-ranging African buffalo (Syncerus caffer). Buffalo that were more resistant to nematode infection had weaker Th1 responses, there was significant genotypic variation in nematode resistance, and anthelminthic treatment enhanced Th1 immunity. Using a disease dynamic model parameterized with empirical data, we found that nematode-induced immune suppression can facilitate the invasion of bovine TB in buffalo. In the absence of nematodes, TB failed to invade the system, illustrating the critical role nematodes may play in disease establishment. Our results suggest that helminths, by influencing the likelihood of microparasite invasion, may influence patterns of disease emergence in the wild.

Does interspecific competition have a moderating effect on Taenia solium transmission dynamics in Southeast Asia?

It is well understood that sociocultural practices strongly influence Taenia solium transmission; however, the extent to which interspecific parasite competition moderates Taenia transmission has yet to be determined. This is certainly the case in Southeast Asia where T. solium faces competition in both the definitive host (people) and the intermediate host (pigs). In people, adult worms of T. solium, T. saginata and T. asiatica compete through density-dependent crowding mechanisms. In pigs, metacestodes of T. solium, T. hydatigena and T. asiatica compete through density-dependent immune-mediated interactions. Here, we describe the biological and epidemiological implications of Taenia competition and propose that interspecific competition has a moderating effect on the transmission dynamics of T. solium in the region. Furthermore, we argue that this competitive ecological scenario should be considered in future research and surveillance activities examining T. solium cysticercosis and taeniasis in Southeast Asia.

CD4 + T cells do not mediate within-host competition between genetically diverse malaria parasites

Ecological interactions between microparasite populations in the same host are an important source of selection on pathogen traits such as virulence and drug resistance. In the rodent malaria model Plasmodium chabaudi in laboratory mice, parasites that are more virulent can competitively suppress less virulent parasites in mixed infections. There is evidence that some of this suppression is due to immune-mediated apparent competition, where an immune response elicited by one parasite population suppress the population density of another. This raises the question whether enhanced immunity following vaccination would intensify competitive interactions, thus strengthening selection for virulence in Plasmodium populations. Using the P. chabaudi model, we studied mixed infections of virulent and avirulent genotypes in CD4+T cell-depleted mice. Enhanced efficacy of CD4+T cell-dependent responses is the aim of several candidate malaria vaccines. We hypothesized that if immune-mediated interactions were involved in competition, removal of the CD4+T cells would alleviate competitive suppression of the avirulent parasite. Instead, we found no alleviation of competition in the acute phase, and significant enhancement of competitive suppression after parasite densities had peaked. Thus, the host immune response may actually be alleviating other forms of competition, such as that over red blood cells. Our results suggest that the CD4+-dependent immune response, and mechanisms that act to enhance it such as vaccination, may not have the undesirable affect of exacerbating within-host competition and hence the strength of this source of selection for virulence.

Tracking the dynamics of pathogen interactions: Modeling ecological and immune-mediated processes in a two-pathogen single-host system

Traditionally, epidemiological studies have focused on understanding the dynamics of a single pathogen, assuming no interactions with other pathogens. Recently, a large body of work has begun to explore the effects of immune-mediated interactions, arising from cross-immunity and antibody-dependent enhancement, between related pathogen strains. In addition, ecological processes such as a temporary period of convalescence and pathogen-induced mortality have led to the concept of ecological interference between unrelated diseases. There remains, however, the need for a systematic study of both immunological and ecological processes within a single framework. In this paper, we develop a general two-pathogen single-host model of pathogen interactions that simultaneously incorporates these mechanisms. We are then able to mechanistically explore how immunoecological processes mediate interactions between diseases for a pool of susceptible individuals. We show that the precise nature of the interaction can induce either competitive or cooperative associations between pathogens. Understanding the dynamic implications of multi-pathogen associations has potentially important public health consequences. Such a framework may be especially helpful in disentangling the effects of partially cross-immunizing infections that affect populations with a pre-disposition towards immunosuppression such as children and the elderly.

The Role of Immune‐Mediated Apparent Competition in Genetically Diverse Malaria Infections

Competitive interactions between coinfecting genotypes of the same pathogen can impose selection on virulence, but the direction of this selection depends on the mechanisms behind the interactions. Here, we investigate how host immune responses contribute to competition between clones in mixed infections of the rodent malaria parasite Plasmodium chabaudi. We studied single and mixed infections of a virulent and an avirulent clone and compared the extent of competition in immunodeficient and immunocompetent mice (nude mice and T cell-reconstituted nude mice, respectively). In immunocompetent mice, the avirulent clone suffered more from competition than did the virulent clone. The competitive suppression of the avirulent clone was alleviated in immunodeficient mice. Moreover, the relative density of the avirulent clone in mixed infections was higher in immunodeficient than in immunocompetent mice. We conclude that immune-mediated interactions contributed to competitive suppression of the avirulent clone, although other mechanisms, presumably competition for resources such as red blood cells, must also be important. Because only the avirulent clone suffered from immune-mediated competition, this mechanism should contribute to selection for increased virulence in mixed infections in this host-parasite system. As far as we are aware, this is the first direct experimental evidence of immune-mediated apparent competition in any host-parasite system.

Immune-mediated interactions during macrophage development in non-Hodgkin's lymphoma.

As part of an investigation of mononuclear phagocytes in malignant lymphoma, measurement of immune-mediated erythrophagocytosis and rosette formation was carried out on cells grown in suspension culture at the monocyte (Day 0) and macrophage (Day 6) stages; the culture medium contained autologous serum. Cells were derived from 10 patients with untreated non-Hodgkin's lymphoma (NHL) and from 12 normal individuals. The results were subjected to Analysis of Variance and demonstrated a significant difference between the two groups with respect to erythrophagocytosis but not to rosette formation. In the NHL group, the proportion of erythrophagocytic cells showed no significant increase between the monocyte and macrophage stages (0.07 to 0.09), in contrast to the marked increase seen in the normal group (0.09 to 0.24). In a pilot investigation to examine the possible role of factors in the serum, cells derived from the NHL patients were cultured with serum from healthy donors; they showed no significant difference in the immune-mediated functions from those grown in autologous serum. Overall, the results provide further quantitative evidence of defective macrophage maturation in NHL, presumably reflecting the compromise of host defence mechanisms.