Cancer: When viruses and bacteria cooperate

Date:
February 24, 2022
Source:
University of Wu"rzburg
Summary:
Infections with several pathogens simultaneously increase the
risk of cervical cancer, according to a new study conducted on
artificial 3D tissue models.



FULL STORY ========================================================================== Patients who develop cervical cancer are often infected not only with
the human papillomavirus (HPV) but also simultaneously with the bacterial pathogen Chlamydia trachomatis. The suspicion is, therefore, that the two pathogens work together in a kind of team to "reprogram" the cells they
infect in such a way that they degenerate and multiply uncontrollably.


==========================================================================
Dr. Cindrilla Chumduri, head of the research group, Department of
Microbiology at the Julius Maximilians University of Wu"rzburg (JMU)
and her team, has now demonstrated for the first time that this is not
just a suspicion but a concretely verifiable effect.

They have developed lifelike organ replicas -- so-called 3D organoids --
on which they investigate the interactions between the pathogens and
the tissues they affect and the disease processes. She has published
the results of her research in the journal Nature Communications.

Multiple infections alter cells.

"Our study uses organoid models to show the danger of multiple infections.

These create a unique cellular microenvironment that potentially
contributes to the reprogramming of tissues and thus to the development
of cancer," says Chumduri, summarizing the central result of her investigations. To do this, the infectious disease biologist used cells
from healthy donors to create an almost physiological organoid model of
the cervix.

In particular, her research focuses on two tissue types: First, the
so-called ectocervix -- the part of the cervical mucosa that extends into
the vagina. And second is the endocervix -- the part of the mucosa that
lines the cervix further inside, connecting the uterus. Their essential
task is to prevent pathogens from entering the uterus and thus help keep
the upper female reproductive tract sterile.



==========================================================================
Why is Chumduri particularly interested in these two types of tissue? "The areas where the ecto- and endocervix merge forms a transition zone and
are particularly prone to infections and neoplasms," she says. Most
cervical cancers originate there, she adds.

HPV and Chlamydia: a malicious alliance driving cellular transformation
There are also valid reasons for focusing on the pathogens HPV and C.

trachomatis: "They are among the most widespread sexually transmitted
pathogen infections," adds Dr. Stefanie Koster, one of the first authors
of the study.

It has long been proven that HPV can cause cancer. That's why girls in
Germany -- and now boys, too -- have been able to get vaccinated against
it since 2007.

In fact, virus DNA can be found in more than 90 percent of all cervical cancers. However, they are not the sole culprit, as shown by the fact
that although more than 80 percent of women become infected with HPV
during their lifetime, not even two percent develop cancer. Coinfection
with C. trachomatis is therefore thought to be a major cofactor in
driving malignant tissue formation. However, "the dynamics of this
coinfection and the underlying mechanisms have been largely unknown,"
adds Dr. Rajendra Kumar Gurumurthy, another first author of the study.

The problem is that "unlike tumor viruses, whose DNA can be found in
tumors, bacteria associated with cancer rarely leave detectable elements
in cancer cells," explains Chumduri. Nevertheless, to link bacteria
to cancer development, she said, it is necessary to identify those
cellular and mutational processes that contribute to cells undergoing pathological changes.

Chumduri and her team have now systematically decoded precisely these
processes in the organoids they have developed.

3D cervical organoids open up new research opportunities The result:
"Our analyses show that HPV and Chlamydia cause a unique cellular
reprogramming of the host," explains the scientist. Several genes are
up-or down-regulated by the two pathogens in different ways, which is associated with specific immune responses. Among other things, pathogens influence a significant subset of all regulated genes responsible for
DNA damage repair.

Overall, the findings show that "co-persistence of HPV and Chlamydia in
a stem cell could adversely affect cellular and genomic stability and
promote neoplastic progression," as the study concludes.

At the same time, the study provides the first evidence that the 3D
organoids of the cervix developed by Dr. Chumduri's group are suitable for studying various aspects of cervical biology, including drug testing under near- physiological conditions. The cultivability of these organoids and
the possibility of genetically manipulating them thus open new avenues
to study the development, progression, and outcome of chronic infections
in an authentic preclinical setting.

========================================================================== Story Source: Materials provided by University_of_Wu"rzburg. Original
written by Gunnar Bartsch. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Stefanie Koster, Rajendra Kumar Gurumurthy, Naveen Kumar, Pon Ganish
Prakash, Jayabhuvaneshwari Dhanraj, Sofia Bayer, Hilmar Berger,
Shilpa Mary Kurian, Marina Drabkina, Hans-Joachim Mollenkopf,
Christian Goosmann, Volker Brinkmann, Zachary Nagel, Mandy Mangler,
Thomas F.

Meyer, Cindrilla Chumduri. Modelling Chlamydia and HPV
co-infection in patient-derived ectocervix organoids reveals
distinct cellular reprogramming. Nature Communications, 2022; 13
(1) DOI: 10.1038/s41467- 022-28569-1 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220224112615.htm

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