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1.  Temporal Association in Hospitalizations for Tuberculosis, Invasive Pneumococcal Disease and Influenza Virus Illness in South African Children 
PLoS ONE  2014;9(3):e91464.
The seasonal variability in hospitalization for tuberculosis may in part relate to super-imposed bacterial or predisposing respiratory viral infections. We aimed to study the temporal association between hospitalization for culture-confirmed pulmonary tuberculosis (PTB), invasive pneumococcal disease (IPD) and influenza virus epidemics in South African children.
We undertook a retrospective analysis which examined seasonal trends, from 2005 to 2008, for hospitalization for culture-confirmed PTB and IPD among children in relation to the influenza epidemics in Soweto, South Africa. Original time-series of the influenza virus epidemics and hospitalization rates for PTB and IPD were decomposed into three components: a trend cycle component, a seasonal component and an irregular component using the X-11 seasonal adjustment method. To compare the seasonality amongst the three series, the trend and irregular components were removed and only seasonal components examined.
Across the study period, the influenza virus epidemics peaked during May to July (winter) months, which was closely followed by an increase in the incidence of hospitalization for IPD (August to October) and PTB (August to November).
Within- and between-year temporal changes associated with childhood TB hospitalization may in part be driven by factors which influence temporal changes in pneumococcal disease, including potential variability in the severity of influenza virus epidemics in temperate climates. The dynamics of the interplay between the host and these infectious agents appears to be complex and multifactorial.
PMCID: PMC3950213  PMID: 24618667
2.  Clinical Epidemiology of Bocavirus, Rhinovirus, Two Polyomaviruses and Four Coronaviruses in HIV-Infected and HIV-Uninfected South African Children 
PLoS ONE  2014;9(2):e86448.
Advances in molecular diagnostics have implicated newly-discovered respiratory viruses in the pathogenesis of pneumonia. We aimed to determine the prevalence and clinical characteristics of human bocavirus (hBoV), human rhinovirus (hRV), polyomavirus-WU (WUPyV) and –KI (KIPyV) and human coronaviruses (CoV)-OC43, -NL63, -HKU1 and -229E among children hospitalized with lower respiratory tract infections (LRTI).
Multiplex real-time reverse-transcriptase polymerase chain reaction was undertaken on archived nasopharyngeal aspirates from HIV-infected and –uninfected children (<2 years age) hospitalized for LRTI, who had been previously investigated for respiratory syncytial virus, human metapneumovirus, parainfluenza I–III, adenovirus and influenza A/B.
At least one of these viruses were identified in 274 (53.0%) of 517 and in 509 (54.0%) of 943 LRTI-episodes in HIV-infected and -uninfected children, respectively. Human rhinovirus was the most prevalent in HIV-infected (31.7%) and –uninfected children (32.0%), followed by CoV-OC43 (12.2%) and hBoV (9.5%) in HIV-infected; and by hBoV (13.3%) and WUPyV (11.9%) in HIV-uninfected children. Polyomavirus-KI (8.9% vs. 4.8%; p = 0.002) and CoV-OC43 (12.2% vs. 3.6%; p<0.001) were more prevalent in HIV-infected than –uninfected children. Combined with previously-tested viruses, respiratory viruses were identified in 60.9% of HIV-infected and 78.3% of HIV-uninfected children. The newly tested viruses were detected at high frequency in association with other respiratory viruses, including previously-investigated viruses (22.8% in HIV-infected and 28.5% in HIV–uninfected children).
We established that combined with previously-investigated viruses, at least one respiratory virus was identified in the majority of HIV-infected and HIV-uninfected children hospitalized for LRTI. The high frequency of viral co-infections illustrates the complexities in attributing causality to specific viruses in the aetiology of LRTI and may indicate a synergetic role of viral co-infections in the pathogenesis of childhood LRTI.
PMCID: PMC3911925  PMID: 24498274
3.  Interrelationship of Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus colonization within and between pneumococcal-vaccine naïve mother-child dyads 
BMC Infectious Diseases  2013;13:483.
A high prevalence of bacterial nasopharyngeal co-infections has been reported in children, however, such data is limited in adults. We examined the interaction of Haemophilus influenzae, Staphylococcus aureus and Streptococcus pneumoniae pharyngeal colonization in mother-child dyads.
Pneumococcal-vaccine naïve children and their mothers had pharyngeal swabs undertaken at 1.6, 2.5, 3.5, 4.5, 7.4, 9.5, 12.5, 16.2 and 24.2 months of child’s age. Swabs were cultured for S. pneumoniae, H. influenzae and S. aureus using standard microbiologic methods. Multivariate generalized estimating equation-models were used to explore the associations of the three bacteria within and between children and their mothers.
In children, the observed probability of co-colonization was higher than expected. Well-defined associations in colonization between the bacteria were observed in children but not among mothers. In children, a synergistic association was observed between S. pneumoniae and H. influenzae (Adjusted odds ratio (AOR): 1.75, 95% CI: 1.32-2.32) and a negative association between S. pneumoniae and S. aureus (AOR: 0.51, 95% CI: 0.39-0.67) or H. influenzae and S. aureus (AOR: 0.24, 95% CI: 0.16-0.34) colonization. Additionally, all three bacteria had a higher likelihood of concurrent colonization. There was a strong association in colonization by the bacteria in children and their mothers, including increased likelihood of maternal colonization if the child was colonized by S. pneumoniae (AOR: 1.84, 95% CI: 1.28-2.63) and H. influenzae (AOR: 6.34, 95% CI: 2.24-18.0).
The effects of immunization of children with pneumococcal-conjugate-vaccine in settings such as ours needs monitoring with regard to potential changes of pharyngeal bacterial ecology which could occur in vaccinated and –unvaccinated age-groups.
PMCID: PMC4015913  PMID: 24134472
Bacterial interaction; Colonization; Pneumococcal conjugate vaccine; Pneumococcus; Staphylococcus aureus; Haemophilus influenzae
4.  How host heterogeneity governs tuberculosis reinfection? 
Recurrent episodes of tuberculosis (TB) can be due to relapse of latent infection or exogenous reinfection, and discrimination is crucial for control planning. Molecular genotyping of Mycobacterium tuberculosis isolates offers concrete opportunities to measure the relative contribution of reinfection in recurrent disease. Here, a mathematical model of TB transmission is fitted to data from 14 molecular epidemiology studies, enabling the estimation of relevant epidemiological parameters. Meta-analysis reveals that rates of reinfection after successful treatment are higher than rates of new TB, raising an important question about the underlying mechanism. We formulate two alternative mechanisms within our model framework: (i) infection increases susceptibility to reinfection or (ii) infection affects individuals differentially, thereby recruiting high-risk individuals to the group at risk for reinfection. The second mechanism is better supported by the fittings to the data, suggesting that reinfection rates are inflated through a population phenomenon that occurs in the presence of heterogeneity in individual risk of infection. As a result, rates of reinfection are higher when measured at the population level even though they might be lower at the individual level. Finally, differential host recruitment is modulated by transmission intensity, being less pronounced when incidence is high.
PMCID: PMC3350683  PMID: 22357260
tuberculosis epidemiology; transmission dynamics; partial immunity; reinfection
5.  Safety, immunogenicity and efficacy of pneumococcal conjugate vaccine in HIV-infected individuals 
Streptococcus pneumoniae is the leading bacterial opportunistic infection in HIV-infected individuals. Anti-retroviral treatment (ART) of HIV-infected individuals reduces their risk of invasive pneumococcal disease (IPD), however, it remains 20- to 40-fold greater compared with age-matched general population. This review summarizes the available published data on the immunogenicity, safety and efficacy of pneumococcal polysaccharide-protein conjugate vaccines (PCV) in HIV-infected children and adults.
Several studies have demonstrated that PCV are safe in the HIV-infected persons. Although PCV are immunogenic in HIV-infected infants, the antibodies produced are functionally impaired, there is possibly a lack or loss of anamnestic responses and immunity declines in later life However, quantitative and qualitative antibody responses to PCV in HIV-infected infants are enhanced when vaccination occurs whilst on ART, as well as if vaccination occurs when the CD4+ cell percentage is ≥ 25% and if the nadir CD4+ is >15%. Although the efficacy of PCV was lower, the vaccine preventable burden of hospitalization for IPD and clinical pneumonia were 18-fold and 9-fold greater, respectively, in HIV-infected children compared with –uninfected children.
In HIV-infected adults, PCV vaccination induces more durable and functional antibody responses in individuals on ART at the time of vaccination than in ART-naive adults, independently of baseline CD4+ cell count, although there does not appear to be much benefit from a second-dose of PCV. PCV has also been shown to reduce the risk of recurrent IPD by 74% in HIV-infected adults not on ART, albeit, also with subsequent decline in immunity and protection.
PMCID: PMC3367711  PMID: 22426374
Streptococcus pneumoniae; HIV; immunogenicity; pneumococcal conjugate vaccine; pneumococcal disease
6.  Persistent High Burden of Invasive Pneumococcal Disease in South African HIV-Infected Adults in the Era of an Antiretroviral Treatment Program 
PLoS ONE  2011;6(11):e27929.
Highly active antiretroviral treatment (HAART) programs have been associated with declines in the burden of invasive pneumococcal disease (IPD) in industrialized countries. The aim of this study was to evaluate trends in IPD hospitalizations in HIV-infected adults in Soweto, South Africa, associated with up-scaling of the HAART program from 2003 to 2008.
Laboratory-confirmed IPD cases were identified from 2003 through 2008 through an existing surveillance program. The period 2003-04 was designated as the early-HAART era, 2005–06 as the intermediate-HAART era and 2007–08 as the established-HAART era. The incidence of IPD was compared between the early-HAART and established-HAART eras in HIV-infected and–uninfected individuals.
A total of 2,567 IPD cases among individuals older than 18 years were reported from 2003 through 2008. Overall incidence of IPD (per 100,000) did not change during the study period in HIV-infected adults (207.4 cases in the early-HAART and 214.0 cases in the established-HAART era; p = 0.55). IPD incidence, actually increased 1.16-fold (95% CI: 1.01; 1.62) in HIV-infected females between the early-and established-HAART eras (212.1 cases and 246.2 cases, respectively; p = 0.03). The incidence of IPD remained unchanged in HIV-uninfected adults across the three time periods.
Despite a stable prevalence of HIV and the increased roll-out of HAART for treatment of AIDS patients in our setting, the burden of IPD has not decreased among HIV-infected adults. The study indicates a need for ongoing monitoring of disease and HAART program effectiveness to reduce opportunistic infections in African adults with HIV/AIDS, as well as the need to consider alternate strategies including pneumococcal conjugate vaccine immunization for the prevention of IPD in HIV-infected adults.
PMCID: PMC3225377  PMID: 22140487
7.  Plasmodium falciparum FIKK Kinase Members Target Distinct Components of the Erythrocyte Membrane 
PLoS ONE  2010;5(7):e11747.
Modulation of infected host cells by intracellular pathogens is a prerequisite for successful establishment of infection. In the human malaria parasite Plasmodium falciparum, potential candidates for erythrocyte remodelling include the apicomplexan-specific FIKK kinase family (20 members), several of which have been demonstrated to be transported into the erythrocyte cytoplasm via Maurer's clefts.
In the current work, we have knocked out two members of this gene family (Pf fikk7.1 and Pf fikk12), whose products are localized at the inner face of the erythrocyte membrane. Both mutant parasite lines were viable and erythrocytes infected with these parasites showed no detectable alteration in their ability to adhere in vitro to endothelial receptors such as chondroitin sulfate A and CD36. However, we observed sizeable decreases in the rigidity of infected erythrocytes in both knockout lines. Mutant parasites were further analyzed using a phospho-proteomic approach, which revealed distinct phosphorylation profiles in ghost preparations of infected erythrocytes. Knockout parasites showed a significant reduction in the level of phosphorylation of a protein of approximately 80 kDa for FIKK12-KO in trophozoite stage and a large protein of about 300 kDa for FIKK7.1-KO in schizont stage.
Our results suggest that FIKK members phosphorylate different membrane skeleton proteins of the infected erythrocyte in a stage-specific manner, inducing alterations in the mechanical properties of the parasite-infected red blood cell. This suggests that these host cell modifications may contribute to the parasites' survival in the circulation of the human host.
PMCID: PMC2909202  PMID: 20668526
8.  Immune Selection and Within-Host Competition Can Structure the Repertoire of Variant Surface Antigens in Plasmodium falciparum - A Mathematical Model 
PLoS ONE  2010;5(3):e9778.
The evolutionary mechanisms structuring the expression pattern of variant surface antigen (VSA) families that allow pathogens to evade immune responses and establish chronic and repeated infections pose major challenges to theoretical research. In Plasmodium falciparum, the best-studied VSA family is erythrocyte membrane protein 1 (PfEMP1). Each parasite genome encodes about 60 PfEMP1 variants, which are important virulence factors and major targets of host antibody responses. Transcriptional switching is the basis of clonal PfEMP1 variation and immune evasion. A relatively conserved subset of PfEMP1 variants tends to dominate in non-immune patients and in patients with severe malaria, while more diverse subsets relate to uncomplicated infection and higher levels of pre-existing protective immunity.
Methodology/Principal Findings
Here, we use the available molecular and serological evidence regarding VSAs, in particular PfEMP1, to formulate a mathematical model of the evolutionary mechanisms shaping VSA organization and expression patterns. The model integrates the transmission dynamics between hosts and the competitive interactions within hosts, based on the hypothesis that the VSAs can be organized into so-called dominance blocks, which characterize their competitive potential. The model reproduces immunological trends observed in field data, and predicts an evolutionary stable balance between inter-clonally conserved dominance blocks that are highly competitive within-host and diverse blocks that are favoured by immune selection at the population level.
The application of a monotonic dominance profile to VSAs encoded by a gene family generates two opposing selective forces and, consequently, two distinct clusters of genes emerge in adaptation to naïve and partially immune hosts, respectively.
PMCID: PMC2842302  PMID: 20339540
9.  5′ flanking region of var genes nucleate histone modification patterns linked to phenotypic inheritance of virulence traits in malaria parasites 
Molecular Microbiology  2007;66(6):1296-1305.
In the human malaria parasite Plasmodium falciparum antigenic variation facilitates long-term chronic infection of the host. This is achieved by sequential expression of a single member of the 60-member var family. Here we show that the 5′ flanking region nucleates epigenetic events strongly linked to the maintenance of mono-allelic var gene expression pattern during parasite proliferation. Tri- and dimethylation of histone H3 lysine 4 peak in the 5′ upstream region of transcribed var and during the poised state (non-transcribed phase of var genes during the 48 h asexual life cycle), ‘bookmarking’ this member for re-activation at the onset of the next cycle. Histone H3 lysine 9 trimethylation acts as an antagonist to lysine 4 methylation to establish stably silent var gene states along the 5′ flanking and coding region. Furthermore, we show that competition exists between H3K9 methylation and H3K9 acetylation in the 5′ flanking region and that these marks contribute epigenetically to repressing or activating var gene expression. Our work points to a pivotal role of the histone methyl mark writing and reading machinery in the phenotypic inheritance of virulence traits in the malaria parasite.
PMCID: PMC2228885  PMID: 18028313

Results 1-9 (9)