Biology subjects

von Gottberg, A.

Publications and source records attributed to von Gottberg, A..

10 recordsLinked to original sources

bioRxiv2026

Identifying candidate genetic determinants associated with invasion in pneumococcal lineages

Serotype invasiveness estimates help identify high-risk serotypes and interpret disease replacement following pneumococcal conjugate vaccination. Because serotype and lineage are strongly associated, their independent contributions must be separated to identify unexpectedly invasive lineages and investigate underlying mechanisms. Using temporally matched carriage and invasive-disease isolates from children aged <7 years in South Africa and the USA, we fitted a logistic mixed-effects model with Global Pneumococcal Sequence Cluster (GPSC) as a random effect and serotype and country as fixed effects. We conducted a species-wide genome-wide association study (GWAS) of invasion and compared the prevalence of significant unitigs in GPSC1 and GPSC21 to identify invasion-associated variants differentiating them. We additionally examined capsule-locus variation that could contribute to their contrasting invasiveness. After serotype and country adjustment, GPSC1 and GPSC21, which both express 19F and share an immediate common ancestor, ranked fifth and 149th of 150 lineages; odds multipliers were 1.51 (95% conditional interval 1.06-2.15) and 0.61 (0.41-0.93), respectively. Of 1,569 invasion-associated unitigs from the species-wide GWAS, 272 differentiated GPSC1 from GPSC21. Among these, the strongest signal mapped to hk11 (desK) and was associated with GPSC1; bgaA was the highest-ranked known antibody-binding target. Within GPSC1 CC271 had additional variants in the ATP-dependent Clp protease ATP-binding subunit ClpX compared to the CC420 subclade. Capsule-protein folds were conserved with local effects indistinguishable from prediction uncertainty. Separating serotype and lineage effects can identify unexpectedly invasive lineages and prioritize candidate serotype-independent determinants, vaccine antigens and capsule variation for experimental investigation.

microbiology↗

bioRxiv2026

Transmission of mutated SARS-CoV-2 variants is favored by relatively prolonged infections due to delayed immunity

SARS-CoV-2 evolution enhanced viral fitness and immune evasion, extending the COVID-19 pandemic and resulting in millions of excess deaths. Viral diversity is generated within infected individuals, yet the timing and interplay of viral and immunological forces that drive transmissible evolution are incompletely understood. We developed a multi-scale within host phylodynamic (WiPhy) model of SARS-CoV-2 infection which couples viral replication, innate and acquired immune responses, and viral mutation. We then validated the model against quantitative viral and phylodynamic metrics. Model output predicts that typical acute infections rapidly generate genetic diversity due to accumulation of minor variants which in most cases do not achieve sufficient concentrations for transmission. Delayed innate immune responses correlate with higher peak viral load and diversification, allowing higher transmission risk of the founder virus or with a novel variant that is equally or less fit. In contrast, the risk of transmitting a fitter variant is highest during the ~10% of infections in which viral loads remain sufficiently high for transmission after 10-14 days. In these cases, non-sustained innate and/or weak acquired immune responses allow sufficient time for selection of a variant with one or more fitness enhancing non-synonymous mutations. Across a simulated cohort of ~1500 individuals, 5% of transmission risk came from variants with enhanced fitness from nonsynonymous mutations, and 13% of simulated infections accounted for 90% of fitter variant transmission risk. Our results highlight how the timing and interplay of viral and immunological forces within a host create bottlenecks that severely limit between host evolution.

evolutionary biology↗

bioRxiv2026

A soluble host signal drives rapid, brain-predominant capsular thickening in Streptococcus pneumoniae via a putative sodium-dependent transporter (SPD_0642) and capsular prepromoter sequence

The Streptococcus pneumoniae capsule is a major determinant of virulence, yet whether bacteria actively remodel it during infection remains unclear. Studying Swiss and South African clinical isolates (serotypes 1, 6B, 8, 12F, 19F, and 35B), we identified a rapid, tissue-specific response: capsule thickness increased within hours upon co-exposure to host cells and tissues. Only two 12F strains failed to thicken. Thickening was greatest in brain tissue, moderate in serum, and absent on the epithelium. This adaptation occurred independently of cod locus phase variation and nutritional factors, and was instead driven by a soluble, thermostable host signal (<3 kDa). Thickening correlated with neuroinflammation but did not require it, as it also occurred in contact with resting brain immune cells. It exacerbated meningitis in mice and enhanced bacteremia. Once induced, capsule thickening dampened inflammatory responses, coinciding with downregulation of pneumolysin, a major pro-inflammatory toxin. Genetic analysis of the non-thickening 12F isolates, together with targeted mutagenesis, identified two independent determinants of capsule-thickness modulation: a specific promoter-proximal element and SPD_0642, a conserved putative transporter encoded outside the capsule operon. Both contributed to the host-induced thickening phenotype. Pneumococci therefore rapidly remodel their surface in response to tissue-specific cues within the host, in a manner distinct from stochastic phase variation outside it. ImportanceMany bacteria are covered by a slimy outer layer, known as a capsule, that helps them evade the immune system. The amount of this layer can influence how easily harmful bacteria cause disease. Until now, scientists knew that bacteria can turn capsule production on or off through changes in their DNA. In this study, we show that Streptococcus pneumoniae, a common cause of serious infections, can also adjust its capsule in another way. It senses soluble signals from the tissues it enters, allowing it to recognize where it is in the body and to gradually change the thickness of its protective outer layer. This finding offers a new way of understanding how bacterial infections develop and may point to new treatment strategies.

microbiology↗

bioRxiv2024

Rapid Emergence and Evolution of SARS-CoV-2 Variants in Advanced HIV Infection

Previous studies have linked the evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic variants to persistent infections in people with immunocompromising conditions1-4, but the evolutionary processes underlying these observations are incompletely understood. Here we used high-throughput, single-genome amplification and sequencing (HT-SGS) to obtain up to [~]103 SARS-CoV-2 spike gene sequences in each of 184 respiratory samples from 22 people with HIV (PWH) and 25 people without HIV (PWOH). Twelve of 22 PWH had advanced HIV infection, defined by peripheral blood CD4 T cell counts (i.e., CD4 counts) <200 cells/L. In PWOH and PWH with CD4 counts [≥]200 cells/L, most single-genome spike sequences in each person matched one haplotype that predominated throughout the infection. By contrast, people with advanced HIV showed elevated intra-host spike diversity with a median of 46 haplotypes per person (IQR 14-114). Higher intra-host spike diversity immediately after COVID-19 symptom onset predicted longer SARS-CoV-2 RNA shedding among PWH, and intra-host spike diversity at this timepoint was significantly higher in people with advanced HIV than in PWOH. Composition of spike sequence populations in people with advanced HIV fluctuated rapidly over time, with founder sequences often replaced by groups of new haplotypes. These population-level changes were associated with a high total burden of intra-host mutations and positive selection at functionally important residues. In several cases, delayed emergence of detectable serum binding to spike was associated with positive selection for presumptive antibody-escape mutations. Taken together, our findings show remarkable intra-host genetic diversity of SARS-CoV-2 in advanced HIV infection and suggest that adaptive intra-host SARS-CoV-2 evolution in this setting may contribute to the emergence of new variants of concern (VOCs).

microbiology↗

bioRxiv2023

Geographic migration and vaccine-induced fitness changes of Streptococcus pneumoniae

Streptococcus pneumoniae is a leading cause of pneumonia and meningitis worldwide. Many different serotypes co-circulate endemically in any one location. The extent and mechanisms of spread, and vaccine-driven changes in fitness and antimicrobial resistance (AMR), remain largely unquantified. Using geolocated genome sequences from South Africa (N=6910, 2000-2014) we developed models to reconstruct spread, pairing detailed human mobility data and genomic data. Separately we estimated the population level changes in fitness of strains that are (vaccine type, VT) and are not (non-vaccine type, NVT) included in the vaccine, first implemented in 2009, as well as differences in strain fitness between those that are and are not resistant to penicillin. We estimated that pneumococci only become homogenously mixed across South Africa after about 50 years of transmission, with the slow spread driven by the focal nature of human mobility. Further, in the years following vaccine implementation the relative fitness of NVT compared to VT strains increased (RR: 1.29 [95% CI 1.20-1.37]) - with an increasing proportion of these NVT strains becoming penicillin resistant. Our findings point to highly entrenched, slow transmission and indicate that initial vaccine-linked decreases in AMR may be transient. One-Sentence SummaryWe describe geographic migration, and fitness dynamics conferred by NVT strains and AMR, for the globally endemic pathogen Streptococcus pneumoniae.

evolutionary biology↗

bioRxiv2022

Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function

Among the 30 non-synonymous nucleotide substitutions in the Omicron S-gene are 13 that have only rarely been seen in other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of the S-gene at sites that will likely impact (i) interactions between subunits of the Spike trimer and the predisposition of subunits to shift from down to up configurations, (ii) interactions of Spike with ACE2 receptors, and (iii) the priming of Spike for membrane fusion. We show here that, based on both the rarity of these 13 mutations in intrapatient sequencing reads and patterns of selection at the codon sites where the mutations occur in SARS-CoV-2 and related sarbecoviruses, prior to the emergence of Omicron the mutations would have been predicted to decrease the fitness of any genomes within which they occurred. We further propose that the mutations in each of the three clusters therefore cooperatively interact to both mitigate their individual fitness costs, and adaptively alter the function of Spike. Given the evident epidemic growth advantages of Omicron over all previously known SARS-CoV-2 lineages, it is crucial to determine both how such complex and highly adaptive mutation constellations were assembled within the Omicron S-gene, and why, despite unprecedented global genomic surveillance efforts, the early stages of this assembly process went completely undetected.

evolutionary biology↗

bioRxiv2021

SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma

SARS-CoV-2 501Y.V2 (B.1.351), a novel lineage of coronavirus causing COVID-19, contains substitutions in two immunodominant domains of the spike protein. Here, we show that pseudovirus expressing 501Y.V2 spike protein completely escapes three classes of therapeutically relevant antibodies. This pseudovirus also exhibits substantial to complete escape from neutralization, but not binding, by convalescent plasma. These data highlight the prospect of reinfection with antigenically distinct variants and foreshadows reduced efficacy of spike-based vaccines.

immunology↗

bioRxiv2019

A novel mosaic tetracycline resistance gene tet(S/M) detected in a multidrug-resistant pneumococcal CC230 lineage that underwent capsular switching in South Africa

SynopsisO_ST_ABSObjectiveC_ST_ABSWe reported a novel tetracycline-resistant gene in Streptococcus pneumoniae and investigated its temporal spread in relation to nationwide clinical interventions.\n\nMethodsWe whole genome sequenced 12,254 pneumococcal isolates from twenty-nine countries on an Illumina HiSeq Sequencer. Serotypes, sequence types and antibiotic resistance were inferred from genomes. Phylogeny was built based on single-nucleotide variants. Temporal changes of spread were reconstructed using a birth-death model.\n\nResultsWe identified tet(S/M) in 131 pneumococcal isolates, 97 (74%) caused invasive pneumococcal diseases among young children (59% HIV-positive, where HIV status was available) in South Africa. A majority of tet(S/M)-positive isolates (129/131) belong to clonal complex (CC)230. A global phylogeny of CC230 (n=389) revealed that tet(S/M)-positive isolates formed a sub-lineage that exhibited multidrug-resistance. Using the genomic data and a birth-death model, we detected an unrecognised outbreak of this sub-lineage in South Africa between 2000 and 2004 with an expected secondary infections (R) of ~2.5. R declined to ~1.0 in 2005 and <1.0 in 2012. The declining epidemic coincided and could be related to the nationwide implementation of anti-retroviral treatment (ART) for HIV-infected individuals in 2004 and PCVs in late 2000s. Capsular switching from vaccine serotype 14 to non-vaccine serotype 23A was observed within the sub-lineage.\n\nConclusionsThe prevalence of tet(S/M) in pneumococci was low and its dissemination was due to an unrecognised outbreak of CC230 in South Africa prior to ART and PCVs. However, capsular switching in this multidrug-resistant sub-lineage highlighted its potential to continue to cause disease in the post-PCV13 era.

microbiology↗

bioRxiv2018

Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, and identified variants in CCDC33 associated with susceptibility. Pneumococcal variation explained a large amount of invasive potential, but serotype explained only half of this variation. Newly developed methods identified pneumococcal genes involved in invasiveness including pspC and zmpD, and allowed a human-bacteria interaction analysis, finding associations between pneumococcal lineage and STK32C.

genomics↗

bioRxiv2018

Global emergence and population dynamics of divergent serotype 3 CC180 pneumococci

Streptococcus pneumoniae serotype 3 remains a significant cause of morbidity and mortality worldwide, despite inclusion in the 13-valent pneumococcal conjugate vaccine (PCV13). Serotype 3 increased in carriage since the implementation of PCV13 in the United States, while invasive disease rates remain unchanged. We investigated the persistence of serotype 3 in carriage and disease, through genomic analyses of a global sample of 301 serotype 3 isolates of the Netherlands3-31 (PMEN31) clone CC180, combined with associated patient data and PCV utilization among countries of isolate collection. We assessed phenotypic variation between dominant clades in capsule charge (zeta potential), capsular polysaccharide shedding, and susceptibility to opsonophagocytic killing, which have previously been associated with carriage duration, invasiveness, and vaccine escape. We identify a recent shift in the CC180 population attributed to a lineage termed Clade II, which was estimated by Bayesian coalescent analysis to have first appeared in 1968 [95% HPD: 1939-1989] and increased in prevalence and effective population size thereafter. Clade II isolates are divergent from the pre-PCV13 serotype 3 population in non-capsular antigenic composition, competence, and antibiotic susceptibility, the last resulting from the acquisition of a Tn916-like conjugative transposon. Differences in recombination rates among clades correlated with variations in the ATP-binding subunit of Clp protease as well as amino acid substitutions in the comCDE operon. Opsonophagocytic killing assays elucidated the low observed efficacy of PCV13 against serotype 3. Variation in PCV13 use among sampled countries was not independently correlated with the CC180 population shift; therefore, genotypic and phenotypic differences in protein antigens and, in particular, antibiotic resistance may have contributed to the increase of Clade II. Our analysis emphasizes the need for routine, representative sampling of isolates from disperse geographic regions, including historically under-sampled areas. We also highlight the value of genomics in resolving antigenic and epidemiological variations within a serotype, which may have implications for future vaccine development.\n\nAuthor SummaryStreptococcus pneumoniae is a leading cause of bacterial pneumoniae, meningitis, and otitis media. Despite inclusion in the most recent pneumococcal conjugate vaccine, PCV13, serotype 3 remains epidemiologically important globally. We investigated the persistence of serotype 3 using whole-genome sequencing data form 301 isolates collected among 24 countries from 1993-2014. Through phylogenetic analysis, we identified three distinct lineages within a single clonal complex, CC180, and found one has recently emerged and grown in prevalence. We then compared genomic difference among lineages as well as variations in pneumococcal vaccine use among sampled countries. We found that the recently emerged lineage, termed Clade II, has a higher prevalence of antibiotic resistance compared to other lineages, diverse surface protein antigens, and a higher rate of recombination, a process by which bacteria can uptake and incorporate genetic material from its surroundings. Differences in vaccine use among sampled countries did not appear to be associated with the emergence of Clade II. We highlight the need to routine, representative sampling of bacterial isolates from diverse geographic areas and show the utility of genomic data in resolving epidemiological differences within a pathogen population.

evolutionary biology↗