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Identification of a two-component signal transduction system that regulates maltose genes in Clostridium perfringens

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Clostridium perfringens is a Gram-positive rod that is widely distributed in nature and is the etiological agent of several human and animal diseases. The complete genome sequence of C. perfringens strain 13 has been determined and multiple two-component signal transduction systems identified. Thomas Hiscox discusses the MalNO system

Image courtesy of interviewee. July 19, 2024

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This video discusses research on *Clostridium perfringens*, focusing on its interaction with host tissues and pathogenicity. The researcher aimed to understand how this bacterium survives and persists within hosts, particularly through nutrient acquisition like maltose utilization. Key components of this process include the MALNO two-component sensor system, which regulates gene expression critical for maltose uptake.

The study began with a genome survey to identify gene regulators affecting pathogenicity and involved generating mutants to assess their role in maltose utilization. The researcher confirmed the function of the MALNO system through transcriptome analyses and biochemical assays, highlighting how environmental changes can influence the expression of genes that aid bacterial survival.

Additionally, the research points out that *C. perfringens* employs a strategy involving toxins that degrade host tissues to liberate nutrients. The bacterium's ability to switch gene expression when transitioning from soil to host environments is crucial for its survival and dissemination.

The researcher notes ongoing investigations into the host-pathogen interface, emphasizing that much remains to be learned about how *C. perfringens* persists without killing its host, which would ultimately jeopardize its survival. Insights from this study may also apply to related human pathogens, suggesting potential overlaps in gene regulatory mechanisms.

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Here are five key points from the video:

1. **Research Focus on Clostridium Perfringens**: The primary interest of the study is to understand how Clostridium perfringens interacts with the host's tissues, particularly looking into the host-pathogen interface and its survival mechanisms within the human body.

2. **Role of the Malano System**: The Malano (MAL N and MAL O) system, a classical two-component sensory histidine kinase system, plays a critical role in regulating the expression of genes necessary for maltose uptake and digestion in Clostridium perfringens, which is important for the bacterium’s pathogenicity.

3. **Nutrient Acquisition in Host Tissues**: The research includes an investigation into factors that influence pathogenicity, particularly how Clostridium perfringens acquires nutrients from host tissues. This involves the upregulation of certain genes and the utilization of maltose as a nutrient source.

4. **Impact of Toxins**: Clostridium perfringens produces various toxins that degrade host tissues, liberating nutrients that the bacterium can then absorb. This reflects a strategy where the bacteria can enhance their survival while residing in the human body.

5. **Ongoing Research and Insights**: The study contributes to a deeper understanding of the mechanisms behind the bacterium's survival and pathogenicity, including its ability to sense environmental changes and adapt gene expression accordingly when switching from soil to host tissues. Ongoing research aims to further explore these interactions and their implications for related bacterial pathogens.

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Here are some key quotes from the video that highlight important aspects of the research on Clostridium perfringens and its interaction with host tissues:

1. **Research Focus:**
- "I was essentially interested in... how Clostridium perfringens interacts with its host pathogen... and how it can survive within human tissues and persist."

2. **Mechanism of Action:**
- "The male NO system is a classical two component sensor histo kinase system... These two proteins work together to regulate the expression of genes in Clostridium perfringens that are required to uptake and digest maltose."

3. **Nutrient Acquisition:**
- "One of those factors important for pathogenicity is the acquisition of nutrients in host tissue... I was essentially looking to see how these regulatory systems worked within Clostridium perfringens."

4. **Experimental Approach:**
- "I generated mutants in Clostridium perfringens, and I identified the male NO system as one system that regulated maltose utilization."

5. **Study Implications:**
- "The implications of this study really give me greater insight into how the bacteria can sense changes in its environment and utilize a wide variety of different nutrients to enhance its survival."

6. **Role of Toxins:**
- "The predominant way [Clostridium perfringens] sources nutrients is through the use of toxins... which can degrade host tissues and free them up so that the bacteria can take them up."

7. **Host Pathogen Dynamics:**
- "Clostridium perfringens is normally found in the soil... but it is an unfortunate human pathogen when it contaminates a wound... It will change the genes that it expresses to maximize its survival."

8. **Balance of Survival and Host Integrity:**
- "It is gotta have this delicate balance between sourcing its nutrients so it can survive and persist, but not just killing the host so it loses its home."

9. **Ongoing Research:**
- "This is ongoing research... I think there’s still a lot more to learn about persistence and about that host pathogen interface."

10. **Related Species:**
- "I think the studies of Clostridium perfringens also help us for related species that are much more ubiquitous human pathogens."

These quotes encapsulate the main ideas of the research regarding Clostridium perfringens, its mechanisms for survival, pathogenicity, and the ongoing nature of the study in understanding the host-pathogen interface.

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Here are a few articles that discuss topics similar to the research on *Clostridium perfringens*, particularly regarding bacterial pathogenicity, host interactions, and nutrient acquisition strategies:

1. **Research on Pathogenic *Clostridium* Species: Mechanisms of Virulence and Host Interaction**
- This article delves into various *Clostridium* species, exploring their virulence factors, including toxin production and nutrient acquisition strategies, and how they adapt to host environments.

2. **Nutrient Acquisition in Bacterial Pathogenesis: The Role of Two-Component Systems**
- This article examines how various bacteria, including *C. perfringens*, utilize two-component regulatory systems to sense nutrient availability and adapt their gene expression for optimal survival within host tissues.

3. **The Impact of Environmental Stressors on Bacterial Virulence Gene Expression**
- Focusing on environmental influences, this study analyzes how changes in the environment can trigger virulence factors in bacteria, discussing specific examples from *Clostridium* species.

4. **Host Defense Mechanisms Against Clostridial Infections: Strategies and Counter-strategies**
- The article reviews the interactions between the host’s immune responses and clostridia, detailing how these bacteria evade host defenses and adapt to survive while reducing lethality.

5. **Comparative Genomics of Pathogenic Bacteria: Insights into Gene Regulatory Networks**
- Discussing comparative genomics, this piece offers insights into how pathogenic bacteria, including *C. perfringens*, regulate genes in response to environmental changes and nutrient availability.

6. **Mechanisms of Nutrient Liberation by Pathogenic Bacteria: The Role of Toxins**
- This research highlights how pathogenic bacteria produce toxins to degrade host tissues for nutrient acquisition, specifically analyzing *C. perfringens* and the biological implications of this strategy.

7. **Adaptation of Bacteria to Host Environments: The Role of Transcriptomics in Understanding Pathogenicity**
- This article emphasizes the use of transcriptomic approaches to study how pathogens like *C. perfringens* adapt their gene expression profiles during transitions between environmental niches.

These articles should provide a comprehensive understanding of similar research themes related to *Clostridium perfringens*, including its pathogenic mechanisms and interactions with host organisms.

X-TIMESTAMP-MAP:LOCAL=00:00:00.000,MPEGTS=900000

00:00.165 --> 00:02.885
I was essentially interested in,

00:03.105 --> 00:06.725
how Clostridium ENSs interacts with its host pathogen,

00:07.505 --> 00:10.885
and I wanted to understand the host pathogen interface

00:10.905 --> 00:12.285
of Clostridium ENSs

00:12.465 --> 00:17.125
and how it can survive within human tissues and persist.

00:17.305 --> 00:21.325
The male nno system is a classical two component sensor

00:21.415 --> 00:22.845
histo kinase system.

00:23.725 --> 00:27.505
Um, MAL N represents the sensor histo kinase,

00:28.005 --> 00:30.545
and mal O represents the response regulator.

00:30.995 --> 00:35.105
These two proteins work together to regulate the expression

00:35.205 --> 00:39.345
of genes in CLOs ring pros that are required to

00:40.325 --> 00:42.705
uptake and digest maltose.

00:42.925 --> 00:47.265
The study was essentially looking at the overall virulence

00:47.265 --> 00:49.545
of Clostridium pro fringes in host tissues.

00:50.125 --> 00:54.105
So initially I started off by doing a genome survey looking

00:54.205 --> 00:58.865
for potential gene regulators that can control,

00:58.865 --> 01:01.065
factors of important for pathogenicity.

01:01.125 --> 01:04.425
So one of those factors important for pathogenicity

01:04.965 --> 01:07.585
is the acquisition of nutrients in host tissue.

01:07.605 --> 01:10.905
So that's how I got interested in, maltose utilization.

01:12.115 --> 01:16.495
And, I was essentially looking to see,

01:17.195 --> 01:21.935
whether, whether how, how these systems work, so

01:21.955 --> 01:24.735
how these regulatory systems worked within Clostridium

01:24.855 --> 01:28.575
frens, then using Muta mutants.

01:28.575 --> 01:30.935
So I generated mutants in Clostridium ence,

01:31.595 --> 01:35.095
and I identified the male NO system as one system

01:35.405 --> 01:38.295
that regulated maltose utilization.

01:39.405 --> 01:42.865
Um, I then further that up with

01:43.375 --> 01:46.145
some transcriptome analysis to confirm

01:46.575 --> 01:50.265
that the Melan o system did indeed regulate maltose maltose

01:50.335 --> 01:53.185
utilization in cost readings,

01:53.485 --> 01:56.385
and then followed that up with sort of biochemical assays.

01:56.885 --> 01:59.825
Um, looking at whether the survival

01:59.925 --> 02:03.225
of Clostridium preens is improved in the presence of maltose

02:03.245 --> 02:05.825
or in the absence of maltose under,

02:05.975 --> 02:07.705
with the various mutants that I generated.

02:08.285 --> 02:10.305
The mutants were really used to

02:10.815 --> 02:12.625
confirm the function of the genes.

02:12.625 --> 02:15.385
But in terms of male o, the implications

02:15.405 --> 02:18.545
of this study really give me greater insight

02:18.545 --> 02:21.425
or give the the world greater insight into

02:21.645 --> 02:25.305
how the bacteria can sense changes in it, its environment,

02:25.765 --> 02:29.625
and utilize a wide variety of different nutrients

02:29.745 --> 02:30.785
to enhance its survival.

02:31.845 --> 02:33.785
Um, and in particular for

02:33.785 --> 02:36.065
what I was particularly interested in was in terms

02:36.065 --> 02:39.305
of the pathogenicity of Clostridium peren.

02:39.765 --> 02:41.345
It gives me an indication of

02:41.655 --> 02:43.865
what strategies the bacterium uses

02:44.125 --> 02:46.465
to source nutrients in host tissues.

02:46.535 --> 02:49.905
Clostridium peren uses a variety of strategies

02:49.905 --> 02:51.505
to source nutrients in its body.

02:52.005 --> 02:55.545
Um, the predominant way is through the use of toxins,

02:55.795 --> 02:58.825
which was another part of research which wasn't explored

02:58.825 --> 02:59.925
In the Malano study.

03:00.385 --> 03:04.485
Um, but essentially Clostridium frens produces a wide

03:04.485 --> 03:08.725
variety of toxins, which can degrade host tissues

03:08.825 --> 03:12.565
and free them up so that the bacteria can take them up.

03:12.585 --> 03:16.485
So it's kind of like, it, it sends out these toxins

03:16.505 --> 03:20.485
to break down host tissues, liberating the little

03:21.325 --> 03:22.445
nutrients for the bacterium

03:22.545 --> 03:25.445
so the bacterium can take up those nutrients and survive.

03:26.465 --> 03:31.405
Um, now my overall research project was looking

03:31.425 --> 03:33.285
at these various variants factors

03:33.305 --> 03:37.045
or these variants, these variants various ways

03:37.145 --> 03:40.165
by which the bacterium can take release resources.

03:40.865 --> 03:43.485
Um, some of that included toxins, which wasn't part

03:43.485 --> 03:44.485
of the Maleo study.

03:45.065 --> 03:48.725
Um, but those toxins do play a role in,

03:49.265 --> 03:50.965
malano functioning.

03:51.095 --> 03:53.645
We've subsequently found out, so this wasn't part

03:53.645 --> 03:57.085
of my work, but what we've subsequently found out is that,

03:57.585 --> 04:00.605
the bacteria has the capacity to

04:01.185 --> 04:04.045
detect when it's in host tissues as opposed

04:04.045 --> 04:05.165
to when it's in the soil.

04:05.545 --> 04:08.925
So Clostridium frens is actually normally found in the soil,

04:09.585 --> 04:14.565
but it is an unfortunate human pathogen when it contaminates

04:14.605 --> 04:17.565
a wound or by some other way, it gets into, in,

04:17.595 --> 04:19.325
into the human body when it's not supposed to.

04:20.395 --> 04:23.765
When that happens, the bacterium can switch its gene

04:23.765 --> 04:26.725
expression, and so when it's in the human body,

04:26.785 --> 04:29.445
it will change the genes that it expresses

04:29.745 --> 04:31.445
to maximize its survival.

04:32.555 --> 04:35.205
Part of that played into my research

04:35.205 --> 04:38.205
where it would upregulate certain toxins

04:38.205 --> 04:41.045
and these toxins liberate nutrients like I talked about,

04:41.265 --> 04:42.965
and then that plays into the uptake

04:43.105 --> 04:46.085
of these nutrients via systems like the Malano system,

04:46.625 --> 04:51.405
but it also plays a role in its spread through the host

04:51.505 --> 04:53.005
and therefore it's dissemination

04:53.185 --> 04:55.405
to potentially another host later on.

04:55.585 --> 04:58.045
The short answer to that question is we frankly don't

04:58.045 --> 04:59.445
know, not yet.

04:59.985 --> 05:02.245
Um, and that that's part of the fun

05:02.245 --> 05:03.925
of this research is we're still trying

05:03.945 --> 05:07.165
to work out the host pathogen interface.

05:07.555 --> 05:11.005
Like I said before, Clostridium preens is normally found in

05:11.005 --> 05:15.885
the soil, so, it's adapted to living in the soil

05:15.985 --> 05:18.445
and it's only an unfortunate consequence

05:18.465 --> 05:21.445
of Clostridium Pro turning up in host tissues.

05:21.475 --> 05:22.965
It's, but it's not really supposed to be there.

05:23.745 --> 05:27.565
So, we're still trying to work out

05:27.745 --> 05:31.165
how does Clostridium fr interact at that,

05:31.785 --> 05:35.205
at the host tissues because it wants to survive,

05:35.305 --> 05:37.925
but it also doesn't want to kill the host

05:37.925 --> 05:40.485
because if it kills the host, then it's out

05:40.485 --> 05:41.565
of a home to live in, right?

05:42.025 --> 05:45.405
So it is gotta have this delicate balance between

05:46.285 --> 05:48.565
sourcing its nutrients so it can survive and persist,

05:48.865 --> 05:52.525
but not just killing the host so it, it loses its home.

05:53.435 --> 05:56.775
And this is ongoing research, by

05:56.775 --> 05:57.775
Other collaborators.

05:57.785 --> 05:59.795
Looking closely at

06:00.295 --> 06:03.155
how genes are regulated at the host pathogen interface,

06:03.595 --> 06:07.915
I think the male o system contributes a small portion

06:07.975 --> 06:11.395
to the overall understanding of how c Clostridium,

06:12.435 --> 06:14.195
maintains itself in host tissues.

06:14.715 --> 06:18.395
I think there's still a lot more to learn about,

06:18.685 --> 06:20.075
about persistence

06:20.135 --> 06:21.955
and about that host pathogen interface

06:21.955 --> 06:22.995
that I talked about before.

06:23.855 --> 06:28.035
Um, I think where I think the studies

06:28.335 --> 06:32.155
or of CPR fringes also helps us for

06:32.825 --> 06:33.955
related species

06:34.305 --> 06:36.995
that are much more ubiquitous human pathogens.

06:36.995 --> 06:40.275
So organisms such as, c Diff,

06:40.325 --> 06:43.555
which is quite common in the uk,

06:44.145 --> 06:48.355
does share quite a few of these gene regulatory systems that

06:48.385 --> 06:49.435
with CFRs.

06:49.615 --> 06:54.235
So there is the potential, for, for overlap

06:54.235 --> 06:57.635
between my studies and, research in that area.

06:57.935 --> 07:01.035
But again, we don't know. We just frankly don't know yet.

07:01.035 --> 07:03.435
And that's, that's areas of ongoing research.

00:00 - I was essentially interested in, how Clostridium ENSs interacts with its host pathogen, and I wanted to understand the host pathogen interface of Clostridium ENSs and how it can survive within human tissues and persist. The male nno system is a classical two component sensor

00:21 - histo kinase system. MAL N represents the sensor histo kinase, and mal O represents the response regulator. These two proteins work together to regulate the expression of genes in CLOs ring pros that are required to uptake and digest maltose. The study was essentially looking at the overall virulence of Clostridium pro fringes in host tissues. So initially I started off by doing a genome survey looking for potential gene regulators that can control,

00:58 - factors of important for pathogenicity. So one of those factors important for pathogenicity is the acquisition of nutrients in host tissue. So that's how I got interested in, maltose utilization. And, I was essentially looking to see, whether, whether how, how these systems work, so how these regulatory systems worked within Clostridium frens, then using Muta mutants. So I generated mutants in Clostridium ence, and I identified the male NO system as one system

01:35 - that regulated maltose utilization. I then further that up with some transcriptome analysis to confirm that the Melan o system did indeed regulate maltose maltose utilization in cost readings, and then followed that up with sort of biochemical assays. looking at whether the survival of Clostridium preens is improved in the presence of maltose or in the absence of maltose under, with the various mutants that I generated.

02:08 - The mutants were really used to confirm the function of the genes. But in terms of male o, the implications of this study really give me greater insight or give the the world greater insight into how the bacteria can sense changes in it, its environment, and utilize a wide variety of different nutrients to enhance its survival. and in particular for what I was particularly interested in was in terms

02:36 - of the pathogenicity of Clostridium peren. It gives me an indication of what strategies the bacterium uses to source nutrients in host tissues. Clostridium peren uses a variety of strategies to source nutrients in its body. the predominant way is through the use of toxins, which was another part of research which wasn't explored In the Malano study. but essentially Clostridium frens produces a wide

03:04 - variety of toxins, which can degrade host tissues and free them up so that the bacteria can take them up. So it's kind of like, it, it sends out these toxins to break down host tissues, liberating the little nutrients for the bacterium so the bacterium can take up those nutrients and survive. now my overall research project was looking at these various variants factors or these variants, these variants various ways by which the bacterium can take release resources.

03:40 - some of that included toxins, which wasn't part of the Maleo study. but those toxins do play a role in, malano functioning. We've subsequently found out, so this wasn't part of my work, but what we've subsequently found out is that, the bacteria has the capacity to detect when it's in host tissues as opposed to when it's in the soil. So Clostridium frens is actually normally found in the soil,

04:09 - but it is an unfortunate human pathogen when it contaminates a wound or by some other way, it gets into, in, into the human body when it's not supposed to. When that happens, the bacterium can switch its gene expression, and so when it's in the human body, it will change the genes that it expresses to maximize its survival. Part of that played into my research where it would upregulate certain toxins and these toxins liberate nutrients like I talked about,

04:41 - and then that plays into the uptake of these nutrients via systems like the Malano system, but it also plays a role in its spread through the host and therefore it's dissemination to potentially another host later on. The short answer to that question is we frankly don't know, not yet. and that that's part of the fun of this research is we're still trying to work out the host pathogen interface.

05:07 - Like I said before, Clostridium preens is normally found in the soil, so, it's adapted to living in the soil and it's only an unfortunate consequence of Clostridium Pro turning up in host tissues. It's, but it's not really supposed to be there. So, we're still trying to work out how does Clostridium fr interact at that, at the host tissues because it wants to survive, but it also doesn't want to kill the host because if it kills the host, then it's out

05:40 - of a home to live in, right? So it is gotta have this delicate balance between sourcing its nutrients so it can survive and persist, but not just killing the host so it, it loses its home. And this is ongoing research, by Other collaborators. Looking closely at how genes are regulated at the host pathogen interface, I think the male o system contributes a small portion to the overall understanding of how c Clostridium,

06:12 - maintains itself in host tissues. I think there's still a lot more to learn about, about persistence and about that host pathogen interface that I talked about before. I think where I think the studies or of CPR fringes also helps us for related species that are much more ubiquitous human pathogens. So organisms such as, c Diff,

06:40 - which is quite common in the uk, does share quite a few of these gene regulatory systems that with CFRs. So there is the potential, for, for overlap between my studies and, research in that area. But again, we don't know. We just frankly don't know yet. And that's, that's areas of ongoing research.

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