Maiumy

Texto final

Using phylogenetic reconstruction to understand the impact of SARS-Cov-2 superspreading on the pandemic

Phylogenies are used to represent the hypothesized evolutionary relationships between lineages. By using them it is possible to reconstruct events that occurred at different time scales. For example, the radiation of flowering plants that occurred millions of years ago, or the evolution of viral sequences in different hosts that occurs in days or weeks. In this last case, phylogenetic reconstructions can be used in epidemiological investigations.

An example of epidemiological investigation where phylogenetic reconstructions were used is a study that uncovered cases of HIV-1 contamination in dental practice in Florida. In 1990 it was discovered that a woman with AIDS had likely been contaminated with HIV-1 during an invasive dental procedure performed by a dentist with AIDS [1]. After that, an epidemiological investigation was launched among former patients of the dentist. The investigation found that five persons with no history of behavioral risk factors for contamination tested positive for HIV-1. Samples from these five persons were collected, and a region of the gene that encodes the envelope of HIV-1 was sequenced. A phylogenetic reconstruction of these sequences was performed, and the sequences of the five patients formed a cluster with the sequence of the dentist as the outgroup [2], as seen in figure 1. The clustering of sequences indicated that the contamination had likely happened during dental practice.

s_2970C95503DD0B5ADC18E803B23860C5059701A58ED9394D3FFB232C2D5CFF7A_1633487491368_image.png

Figure 1: phylogenetic reconstruction of the sequences from the five patients who had no history of behavioral risk factors for HIV-1 contamination (Patients A, B, C, E, and G). X and Y indicate the most divergent sequences from each person. LC designates the local controls used, sequences from patients in the same area but that were not related to the case. In the dotted area is the cluster formed by the sequences of the five patients with the dentist’s sequence as outgroup (Ou et al, 1992.)

A small number of hosts being responsible for a disproportionate number of new infections is an event observed in pathogen transmission, and known as superspreading. It occurs in the transmission of diseases such as Ebola, smallpox, and tuberculosis [4]. Recently, superspreading was detected occurring in the transmission of SARS-CoV-2 [3-9]. In one of these cases, an asymptomatic fitness trainer from Hong Kong tested positive for SARS-CoV-2 infection. This prompted an epidemiologic investigation, and contact tracing was used to identify people who had had contact with him. Out of the 300 people who had visited the fitness center where the trainer worked, 102 tested positive for SARS-CoV-2. Samples from 59 of these patients were sequenced and used in a phylogenetic reconstruction of the viruses detected in the fitness center [9]. All the 59 samples formed a cluster (figure 2), in a sister group to the local controls used. That means that the sequences from these 59 patients were more similar to each other than to other SARS-CoV-2 sequences from the same location, indicating that a superspreading event had likely taken place at the fitness center.

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Figure 2: Phylogenetic tree of SARS-CoV-2 viruses sampled from persons who frequented the fitness center. Sequences from other samples (clades L, O, S, V, G, GR, and part of GH) were also included in the analysis. Clade GH comprises the fitness center samples and the local controls used. Local controls were sequences sampled at the same area and time interval but unrelated to the fitness center (Chu et al, 2021.)

Other epidemiological investigation studies focused on superspreading were conducted during the pandemic. Two of them used hundreds of samples to reconstruct the phylogenetic trees of SARS-CoV-2 in different locations [3,7]. One of them concluded that a disproportionately small number of transmission events accounted for the majority of local transmission during the early outbreak in the Boston area [3]. The same study also traced 50.000 cases in the United States, Australia, and Europe to a single superspreading event at a business conference in Boston. Other studies investigated the role of superpreading events in the early outbreak in Wuhan [6] and in the emergence of variants [5].

It is inherent to the methods of phylogenetic reconstruction that sequences that are more closely related to each other form clusters. The time scale of the events represented on a phylogenetic tree depends on the data used in its inference. Because of that, phylogenetic reconstructions inferred from sequences sampled from different patients contaminated with a pathogen give insight into the viral sequence evolution in different hosts. If the samples are taken at a determined location and time interval, clusters of sequences might indicate that a superspreading event took place. With sequencing initiatives, and consequent data processing and interpretation, it was possible to use phylogenetic reconstructions to understand the dynamics of SARS-CoV-2 superspreading and gain insights into its impact on the pandemic.

References
[1]Myers, G. (1994). Molecular investigation of HIV transmission. Annals of internal medicine, 121(11), 889-890.
[2] Ou, C. Y., Ciesielski, C. A., Myers, G., Bandea, C. I., Luo, C. C., Korber, B. T., … & Epidemiologic Investigation Group. (1992). Molecular epidemiology of HIV transmission in a dental practice. Science, 256(5060), 1165-1171.
[3] Lemieux, J. E., Siddle, K. J., Shaw, B. M., Loreth, C., Schaffner, S. F., Gladden-Young, A., … & MacInnis, B. L. (2021). Phylogenetic analysis of SARS-CoV-2 in Boston highlights the impact of superspreading events. Science, 371(6529), eabe3261.
[4] Lewis, D. (2021). Superspreading drives the COVID pandemic-and could help to tame it. Nature, 544-546.
[5] Gómez-Carballa, A., Pardo-Seco, J., Bello, X., Martinón-Torres, F., & Salas, A. (2021). Superspreading in the emergency of COVID-19 variants. Trends in Genetics.
[6] Wang, L., Didelot, X., Yang, J., Wong, G., Shi, Y., Liu, W., … & Bi, Y. (2020). Inference of person-to-person transmission of COVID-19 reveals hidden super-spreading events during the early outbreak phase. Nature communications, 11(1), 1-6.
[7] Popa, A., Genger, J. W., Nicholson, M. D., Penz, T., Schmid, D., Aberle, S. W., … & Bergthaler, A. (2020). Genomic epidemiology of superspreading events in Austria reveals mutational dynamics and transmission properties of SARS-CoV-2. Science translational medicine, 12(573).
[8] Chau, N. V. V., Hong, N. T. T., Ngoc, N. M., Thanh, T. T., Khanh, P. N. Q., Nguyet, L. A., … & Van Tan, L. (2021). Superspreading Event of SARS-CoV-2 Infection at a Bar, Ho Chi Minh City, Vietnam. Emerging infectious diseases, 27(1), 310.
[9] Chu, D. K., Gu, H., Chang, L. D., Cheuk, S. S., Gurung, S., Krishnan, P., … & Poon, L. L. (2021). SARS-CoV-2 Superspread in Fitness Center, Hong Kong, China, March 2021. Emerging infectious diseases, 27(8), 2230.

Autoavaliação

Ao me matricular na disciplina meu principal objetivo era ter um contato mais sistematizado com os conteúdos abordados, e também de sedimentar esses conteúdos por meio das atividades propostas. De forma geral, acredito que alacancei esses objetivos. Acredito que eu poderia ter me dedicado mais à leitura da bibliografia proposta, pois isso teria resultado em um entendimento mais aprofundado dos assuntos. Entretanto, como essa é uma disciplina introdutória, acredito que "descobrir o que eu preciso aprender" para que eu possa explorar mais esses conteúdos posteriormente foi muito produtivo também. Por isso, acredito que a nota consistente com meu desempenho e objetivos é nota 1.

2021-10-04

1. Seleção de um tema delimitado

Ideias iniciais e potenciais problemas

- How phylogenetic reconstruction helps us understand the origins of the pandemic.
(Muito amplo, delimitar mais)

Refs. possíveis:
https://www.pnas.org/content/117/17/9241?fbclid=IwAR3UkvDWD4g9gMaWqBWflcUw0um34tIn1dzp_aH8A0SCplyXU4ihVnb78mM

- How phylogenetic reconstruction helps us understand the rise of SARS-CoV-2 variants.
(Delimitar mais, possivelmente focar em uma das variantes—delta?)

- Difficulties and problems in the analysis and interpretation of SARS-CoV-2 phylogenies.
(Envolve bastante metodologia. Provavelmente preciso delimitar mais.)

Refs. possíveis:
https://academic.oup.com/mbe/article/38/5/1777/6030946
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009175

How phylogenetic reconstructon helps us understand superspreading.
(ACHO que esse tema é o que tem o recorte mas apropriado até então, mas acho talvez seja possível e necessário delimitar mais.)

Refs. possíveis:
https://www.science.org/doi/full/10.1126/science.abe3261
https://www.nature.com/articles/d41586-021-00460-x
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30462-1/fulltext
https://www.sciencedirect.com/science/article/pii/S0168952521002626
https://www.nature.com/articles/s41467-020-18836-4

2. Tema "final" escolhido: Using phylogenetic reconstruction to understand the impact of SARS-Cov-2 superspreading in the pandemic

(Sujeito à mudança.)

Outline v1

Introduction
- In superspreading events one infected individual infects many others.
<Something more about the phenomenon itself.>
- One way of detecting these events is by constructing phylogenetic trees of the samples of infected individuals.

Dev 1 - How phylogenies are in fact used to detect superspreading.

Dev 2 - Case study + Numbers about superspreading
- Use the Boston one? Look for others? One that happened in Brazil?
- Pick one example that is easy to understand and summ up, and that is representative, and then "generalize" to impress the relevance of this phenomenon in the pandemic.

Dev 3???
<Not sure if it's necessary. I will decide that on my next outline.>

Conclusion
- Superspreading events are relevant to Covid transmission. Understanding how to identify them is important. Phylogenetic reconstructions offer a way of detecting and understanding superspreading.

Refs
https://www.science.org/doi/full/10.1126/science.abe3261
https://www.nature.com/articles/d41586-021-00460-x

2021-10-05

Outline v2

Intro
- Phylogenetic reconstructions can be used to infer evolutionary relationships between lineages at different time scales.
- For example, the relationships between major clades that diverged million years ago.
- Or, to infer the evolutionary proximity between viral sequences that infected two or more different hosts.
- In this case, phylogenetic reconstructions can be used in epidemiological investigations.

Dev 1

(Too detailed, revise this later).
(First paragraph?)

- One example of phylogenetic reconstruction being used in epidemiological investigations is that of a case of HIV-contamination in dental practice.
- In 1990, it was discovered that a woman with AIDS had likely been contaminated with HIV-1 during an invasive dental procedure performed by a dentist with AIDS [1].
- After this case was reported an epidemiological investigation was launched [2].
- Out of the 1100 former patients that were investigated, seven were contaminated with HIV-1.
- Of these seven patients, five did not exhibit behavioral risk factors for contamination. Thus, it was likely that they had been infected during dental procedure.
- The sequences of a region of the gene that codes the envelope of HIV-1 of the seven patients were sequenced.
- The samples of these patients were compared to those of the dentist and other infected people who lived in the same area but were unrelated to the case.
- The phylogenetic analysis indicated that the five patients formed a cluster, with the sequence of the dentist forming the outgroup (Figure 1).

Dev 2
- Another example of epidemiologic investigation in which phylogenetic reconstruction was used is the detection of SARS-Cov-2 superspreading.
- Superpreaders are individuals who contribute disproportionately with new infections [reference].
- In a superspreading event, a small part of the individuals account for the majority of the infections (Figure 3).
- A phylogenomic reconstruction using 772 complete genomic sequences of SARS-CoV-2 from the early outbreak in Boston uncovered that although there were 120 cases of SARS-CoV-2 introduction into the Boston area, 85% of the local transmission was due to only 29% of the introductions (figure 4) [3].
- At least two superspreading events were identified in Boston at that time period: one occurred in a nursing facility, and the other at a business conference.
- 28 of the conference atendees sequenced had the C2416T lineage.
- The C2416T lineage was widespread in Europe before the event.
- After the conference, it accounted for 30-46% of the viral genomes studied in the Boston area.
- This lineage was then detected in studies in 29 US states, Europe and Australia.
- The study inferred that 100 cases resulted directly from the meeting, and that 50.000 were linked to the conference.

Dev 3
- Other SARS-CoV-2 superspreading events were observed [references], including during the early outbreak in Wuhan [reference].

Conclusion
- Superspreading events were relevant to SARS-CoV-2 transmission, and had a significant (use this word?) impact in the Covid-19 pandemic [reference].
- Phylogenetic reconstructions inherently offer a way of detecting these events.

References
[1] Morbid. Mortal. Wkly. Rep. 39, 489 (1990).
[2] Molecular Epidemiology of HIV Transmission in a Dental Practice.
[3] Phylogenetic analysis of SARS-CoV-2 in Boston highlights the impact of superspreading events
[4] Superspreading drives the COVID pandemic — and could help to tame it. (Nature)
[5] Superspreading in the emergence of COVID-19 variants. (Trends in Genetics)
[6] Inference of person-to-person transmission of COVID-19 reveals hidden super-spreading events during the early outbreak phase. (Nature)

2021-10-06

Final outline

Intro (Introduce the idea that phylogenies can be used in epidemiological investigations)
- Phylogenetic reconstructions can be used to infer evolutionary relationships between lineages at different time scales.
- For example, the relationships between major clades that diverged million years ago.
- Or, to infer the evolutionary proximity between viral sequences that infected two or more different hosts.
- In this case, phylogenetic reconstructions can be used in epidemiological investigations.

Dev 1 (Case study 1 - explain how the grouping in the phylogeny traces the infection back to one host.)
- Case study: epidemiological investigation in the case of tracing back patients contaminated with HIV-1 during dental procedures.
- env gene was sequenced.
- The HIV-1 (env gene) sequences of five patients of the same dentist were closer to each other, with the sequence from the dentist being the outgroup (Fig. 1).

Dev 2 (Case study 2 - Clarify the thing about the C2146T lineage and how it traces back to the superspreading event in the conference.)

- Such an event, in which one host is responsible for a disproportionate number of new infections (Fig. 3) is a common (?) event in pathogen transmission, and occurs naturally (?).
- For example, with Ebola, smallpox and tuberculosis [4].
- These are called superspreading events, and recently, they were relevant in the Covid-19 pandemic.
- A phylogenomic reconstruction using 772 complete genomic sequences of SARS-CoV-2 from the early outbreak in Boston uncovered that although there were 120 cases of SARS-CoV-2 introduction into the Boston area, 85% of the local transmission was due to only 29% of the introductions (figure 4) [3].
- At least two superspreading events were identified in Boston at that time period: one occurred in a nursing facility, and the other at a business conference.
- 28 of the conference atendees sequenced had the C2416T lineage.
- The C2416T lineage was widespread in Europe before the event.
- After the conference, it accounted for 30-46% of the viral genomes studied in the Boston area.
- This lineage was then detected in studies in 29 US states, Europe and Australia.
- The study inferred that 100 cases resulted directly from the meeting, and that 50.000 were linked to the conference.

Dev 3 (????????? Connect the phylogenetic reconstruction with the mechanisms of transmission)
- Other SARS-CoV-2 superspreading events were observed [5, 6, 7], including during the early outbreak in Wuhan [6], and connected to the emergence of variants [5].
- The biology of SARS-CoV-2 favours (?) superspreading [ref.], which can, then, be visualized in the phylogenies.

Conclusion (Highlight that as a consequence of how phylogenies work we can detect superspreading by the way the sequences from different hosts group together.)

- Superspreading events were relevant to SARS-CoV-2 transmission, and had a significant (use this word?) impact in the Covid-19 pandemic [references - 3, 4, 5, 6, others].
- Phylogenetic reconstructions inherently offer a way of detecting these events.

References
[1] Morbid. Mortal. Wkly. Rep. 39, 489 (1990).
[2] Molecular Epidemiology of HIV Transmission in a Dental Practice.
[3] Phylogenetic analysis of SARS-CoV-2 in Boston highlights the impact of superspreading events
[4] Superspreading drives the COVID pandemic — and could help to tame it. (Nature)
[5] Superspreading in the emergence of COVID-19 variants. (Trends in Genetics)
[6] Inference of person-to-person transmission of COVID-19 reveals hidden super-spreading events during the early outbreak phase. (Nature)
[7] Genomic epidemiology of superspreading events in Austria reveals mutational dynamics and transmission properties of SARS-CoV-2 (Science)
[8] Superspreading Event of SARS-CoV-2 Infection at a Bar, Ho Chi Minh City, Vietnam (Emerging infectious diseases).
[9] SARS-CoV-2 Superspread in Fitness Center, Hong Kong, China, March 2021.


Lista de figuras possíveis.

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(Figure 1)

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(Figure 2)

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(Figure 3)

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(Figure 4)

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(Superspreading Event of SARS-CoV-2 Infection at a Bar, Ho Chi Minh City, Vietnam)

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