Lecture 14 - Co-Infections in the Host PDF

Co-infections in the host  Outline of today’s lecture Definition of co-infection Define facilitation and competition (outcomes of co-infection) Competition between strains reduces their transmission Immunosuppressive viruses facilitate co-infection by other pathogens...

Co-infections in the host  Outline of today’s lecture Definition of co-infection Define facilitation and competition (outcomes of co-infection) Competition between strains reduces their transmission Immunosuppressive viruses facilitate co-infection by other pathogens HIV and tuberculosis in humans Bovine respiratory disease in cattle Treatment of co-infections can have unexpected consequences Effect of deworming on R0 of bovine tuberculosis in African buffalo  Co-infection is when a host is infected with multiple parasite/pathogen species Co-infection (or mixed infection or multi-strain infection) is when host is infected with multiple strains of the same parasite/pathogen species  Each host species has many different species of parasites/pathogens Each host species is infected with many different parasite/pathogen species Rodent host has 18 different parasites Bacteria, protozoans, nematodes, cestodes, fleas, and ticks Most host organisms are infected with multiple parasite species at same time Co-infections with different parasite species are the norm  Prevalence of multi- strain infections for human pathogens Study on prevalence of multi-strain infections for 62 human pathogens Mean prevalence of multi-strain infections is 20% in human patients Some pathogens (e.g. influenza) have low prevalence of multi-strain infections Some parasites (e.g. malaria) have high prevalence of multi-strain infections (>80%) Multi-strain pathogens are common in humans and probably in other hosts too! Co-infection leads to interactions between parasites Co-infected hosts carry multiple parasite species or parasite strains These parasite species or parasite strains can interact inside the host Interactions include competition and facilitation Competition: parasite A reduces fitness of parasite B (and/or vice versa) Facilitation: parasite A enhances fitness of parasite B (and/or vice versa) Question: How do we determine whether parasite species in co- infection are experiencing competition or facilitation?  Competition versus Facilitation How do we determine the interaction between two parasite species? Determine abundance of parasite X and parasite Y when they are alone in host Determine abundance of X and Y when they are together in co-infected host Null hypothesis: If no competition, abundance in co-infection is the sum of parasites X and Y when alone Facilitation: abundance in co-infected host > abundance when alone in host Competition: abundance in co-infected host Time = 8:40 AM < abundance when alone in host  Competition and niche overlap Ecological niche = conditions and resources organism requires to exist Niche overlap: 2 species have similar niches (e.g., host tissues, host resources) Niche overlap causes competition over limited resources Strength of competition depends on degree of niche overlap Question: What is the expected relationship between genetic relatedness of parasites, niche overlap, and strength of competition?  Co-infection and competition between pathogen strains can reduce their infection and transmission success  Competition between strains of B. afzelii in the rodent host Study whether competition between pathogen strains exists Tick-borne pathogen, Borrelia afzelii, has rodent reservoir hosts and causes LD Test if competition influences prevalence of each strain in rodent host tissues Borrelia afzelii Apodemus sylvaticus Test if competition in rodent host influenced strain transmission to feeding ticks Experimental design for measuring competition Expt 1 – focal strain = FIN Expt 2 – focal strain = CH Single infection Co-infection Single infection Co-infection FIN (n = 10) FIN + CH (n = 10) CH (n = 10) CH + FIN (n = 10) Competition between B. afzelii strains in rodent Finnish strain Swiss strain tissues Two strains of B. afzelii are Fin-Jyv-A3 and NE4049 Test presence of two strains in 6 tissues Strain Fin-Jyv-A3 negatively affected by competitor strain NE4049 Finnish strain alone found in 75% of tissues In co-infected mice, Finnish strain found in 90% 0.2 0.2 Presence of strain NE4049 reduced 0.0 0.0 transmission of strain Fin-Jyv-A3 to 60% Alone Co−infection Alone Co−infection Reduction in transmission is evidence of competition (left panel) Co-infection and competition reduce strain- specific transmission success Facilitation – HIV and TB  Global HIV Prevalence and TB incidence in 2007 HIV prevalence rates are positively correlated with tuberculosis (TB) incidence across 132 countries Countries with high prevalence of HIV have high incidence of tuberculosis Question: Why is the prevalence of HIV positively correlated with the incidence of TB across 132 countries? Kwan. 2011. Clin Micro Rev 24:351-376 HIV increases susceptibility to TB Time = 8:50 AM Study on miners in South Africa and their HIV and TB status over 7 years Study had 23,874 miners of which 14.1% (3371) were HIV-positive X-axis is time (in years) and Y-axis is % of miners that acquired TB over time In HIV-positive miners, TB incidence rate was 2.90 cases/100 person-years at risk In HIV-negative miners, TB incidence rate was 0.80 cases/100 person-years at risk Facilitation: HIV increases susceptibility of humans to acquire TB by factor of 3.6 Sonnenberg. 2005. JID 191:150-158.  Question: What are the consequences of co-infection on mortality rates?  Global Incident TB Cases and TB-Related Deaths in 2008 HIV-associated tuberculosis (TB) contributes disproportionately to TB-related deaths 2008: HIV-associated TB accounts for 15% of incident TB, but contributes to 29% of deaths among incident TB cases Case fatality rate (CFR) for patients with TB alone is 16%, whereas CFR for patients co-infected with TB and HIV is 37% Presence of HIV doubled the CFR of TB Example of how co-infection with multiple pathogens can worsen disease outcomes Kwan. 2011. Clin Micro Rev 24:351-376  Veterinary example - Bovine respiratory disease  Bovine respiratory disease (BRD) Bovine respiratory disease (BRD) or “shipping fever” occurs in young calves entering commercial feedlots BRD responsible for 75% of morbidity and 50% to 70% of mortality observed in feedlots BRD costs American cattle industry ~1 billion USD per year BRD is caused by complex of viral and bacterial pathogens (co- infection) linked to stressors associated with management  Stress on the feedlot Beef calves (9 to 11 months) are separated from moms and transported to feedlot resulting in stress, which suppresses calf immune system High density and comingling during transport and in feedlot facilitates pathogen exposure and transmission BRD is identified by clinical signs including lethargy, nasal discharge, distressed breathing, and body temperature > 40.5 ºC BRD associated with co-infections of viruses, bacteria, and nematode parasites Infectious disease triangle: Stress, pathogens, and environment interact to cause BRD in weaned calves in feedlot  Bovine respiratory disease in cattle is associated with numerous viruses and bacteria Five viral pathogens: BRSV, BoHV-1, BVDV, PI-3, and BCoV Four bacteria: Pasteurella multocida, Mannheimia haemolytica, Mycoplasma bovis, Histophilus somni Duration of viral infections is short (< 2 weeks) Bacteria may be commensal members of the microbiome of URT BRD starts with primary viral infection followed by secondary bacterial infection Bacteria migrate from upper to lower respiratory tract causing pneumonia Time = 9:00 AM  BRD bacteria present in sick and healthy cattle Drag image to reposition. Double click to magnify further. Compare bacterial microbiome in weaned calves with BRD versus healthy controls BRD clinical signs: lethargy, nasal discharge, distressed breathing, and body temperature > 40.5 ºC Nasopharyngeal swabs used to sample bacterial microbiome and 16S rRNA sequencing Relative abundance of bacterial taxa in upper respiratory tract Calves with BRD surrounded by red boxes Mycoplasma bovis and Mannheimia hemolytica were found in both sick and healthy calves McDaneld (2018) J Anim Sci 96:1281–1287  Bovine viral diarrhea virus (BVDV) is associated with bovine respiratory disease (BRD) Bovine viral diarrhea virus (BVDV) is associated with bovine respiratory disease (BRD) BVDV infection results in persistently infected and acutely infected calves; both have higher incidence of BRD BVDV suppresses cattle immune system. Virus kills lymphocytes and reduces their function Infection with BVDV makes calf susceptible to other respiratory pathogens resulting in BRD  Calves exposed to BVDV are more likely to develop bovine respiratory disease (BRD) Test if BVDV increases risk of BRD in feedlot 2000 calves in 20 pens (100 calves/pen); 9 exposed pens and 11 control pens Calves persistently infected with BVDV placed inside pens with uninfected pen mates Risk of treatment for BRD was 43% higher in calves exposed to PI calf versus calves not exposed to PI calf Study suggests that infection with BVDV increases risk of BRD in cattle Limitation of study: no testing of respiratory pathogens in the lungs Loneragan. 2005. J Am Vet Med Assoc 226:595–601.  Summary of BRD in cattle BRD is most important disease in North American cattle industry. Occurs in calves upon arrival at feedlot. BRD based on clinical signs (depression, lethargy, temperature). BRD associated with co-infection of several viral and bacterial pathogens. Separation from moms, transport, new environment cause stress. Stress and/or viral infection suppress immune system, which drives bacterial dysbiosis in lower respiratory tract, which causes BRD Treatment of co- infections – unintended consequences  African buffalo, tuberculosis, and nematode parasites Study on wild African buffalo in Hluhluwe- iMfolozi Park, in South Africa Buffalo are naturally infected with GI nematodes (Haemonchus, Cooperia, and Africanastrongylus) Buffalo are also infected with M. bovis, which causes bovine tuberculosis (BTB) Many buffalo have co-infections with GI nematodes and M. bovis Nematodes and M. bovis found in GI tract versus respiratory tract Worms reduce body condition in TB-infected buffalo Time = 9:10 AM Parasites have negative effects on host fitness (by our ecological definition) Buffalo fitness: body condition = amount of body fat on buffalo Worm infection associated with poor body condition in TB-positive hosts but not in TB-negative hosts Co-infected buffalo have lower body condition compared to other 3 groups Parasites have synergistic negative effects on the host where whole is greater than sum of its parts Ezenwa. 2015. Science 347:175-177  De-worming African buffalo and bovine BTB Does de-worming buffalo infected with M. bovis influence their mortality rate? Captured 216 buffalo; split into control group and deworming treatment group At start, nematode prevalence is the same between the two groups (>50%). Treated group was de-wormed with anthelmintic. De-worming treatment was effective. Control group was left alone. All buffalo were BTB-negative at start of study. At end of 4-year study, ~1/3 of buffalo had acquired BTB. Prevalence of BTB was similar between de-wormed group and control group. Predict effect of deworming treatment on survival of BTB-infected buffalo  Survival of BTB-infected buffalo in control and dewormed groups For BTB-infected buffalo, compare survival between dewormed and control groups Survival curves show proportion of BTB-infected buffalo surviving over time For BTB buffalo, mortality rate of control group was ~9x higher than dewormed group GI nematodes increase mortality rate of BTB-infected buffalo Deworming treatment worked! Increased survival of BTB-infected buffalo! Question: How does enhanced survival of BTB- infected animals influence R0 of BTB? Ezenwa. 2015. Science 347:175-177  R0 of M. bovis in control and dewormed buffalo R0 for treated buffalo (15.5) is 8x higher compared to control buffalo (2.0) In control group, co-infected buffalo die quickly, which reduces BTB transmission In treated group, deworming allows BTB-infected buffalo to live longer, which enhances transmission of BTB Summary: deworming treatment increases R0 of BTB in buffalo population Deworming buffalo has bad outcome of increasing transmission and prevalence of BTB! Ezenwa. 2015. Science 347:175-177  Why is R0 higher for dewormed buffalo? For BTB-infected buffalo, mortality rate was 9x higher for the worm-normal (control) group compared to dewormed (treated) group In worm-normal (control) group, the R0 of BTB was low because buffalo co- infected with M. bovis and nematode worms die quickly, which reduces BTB transmission In dewormed (treated) group, the R0 of BTB was high because deworming enhances survival of BTB-infected buffalo, which increases BTB transmission This study shows that what is good for the individual and what is good for the population (i.e., public health) are often in conflict  Summary of co-infection Definition of co-infection. Definition of facilitation and competition. Examples of how immunosuppressive viruses facilitate co-infection by other pathogens HIV and tuberculosis in humans Bovine respiratory disease in cattle and bovine viral diarrhea virus Treatment of co-infections can have unexpected consequences Deworming of wild buffalo enhances R0 of bovine tuberculosis End of course Time = 9:20 AM  Pathogens in calves that died of BRD Drag image to reposition. Double click to magnify further. IHCStainin Study on BRD in 90 feedlot calves in Western Canada. Calves died within 60 days of entering feedlot 100% BRD classified into 5 categories: peracute, acute, 80% subacute, bronchiolar, chronic animals Immunohistochemistry (IHC) of lung tissues found 60% Mannheimia haemolytica (M; dark blue), Mycoplasma bovis (M; yellow), bovine viral diarrhea virus (BVDV; red), and more Mannheimia haemolytica (M; dark blue) and Mycoplasma bovis (M; yellow) were most common agents in fatal BRD cases onchiolar (n=10) Chronic (n=18) C IHC gives presence/absence of pathogens but not their abundance in lungs Difficult to assign causality Booker. 2008. Can Vet J 49(5):473–81.  HIV is a driver of TB epidemic in USA HIV is driver of TB at population level USA: TB incidence declined from 1980- 1985 but increased 20% from 1985-1992 HIV epidemic ~ 51,700 excess TB cases HIV facilitates TB in human populations HIV makes it easier for tuberculosis to spread through human populations Presence of HIV increases the R0 of tuberculosis