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9. 13: Viral Ecology - Biology

9. 13: Viral Ecology - Biology


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9. 13: Viral Ecology

Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity

The papain-like protease PLpro is an essential coronavirus enzyme that is required for processing viral polyproteins to generate a functional replicase complex and enable viral spread 1,2 . PLpro is also implicated in cleaving proteinaceous post-translational modifications on host proteins as an evasion mechanism against host antiviral immune responses 3-5 . Here we perform biochemical, structural and functional characterization of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PLpro (SCoV2-PLpro) and outline differences with SARS-CoV PLpro (SCoV-PLpro) in regulation of host interferon and NF-κB pathways. SCoV2-PLpro and SCoV-PLpro share 83% sequence identity but exhibit different host substrate preferences SCoV2-PLpro preferentially cleaves the ubiquitin-like interferon-stimulated gene 15 protein (ISG15), whereas SCoV-PLpro predominantly targets ubiquitin chains. The crystal structure of SCoV2-PLpro in complex with ISG15 reveals distinctive interactions with the amino-terminal ubiquitin-like domain of ISG15, highlighting the high affinity and specificity of these interactions. Furthermore, upon infection, SCoV2-PLpro contributes to the cleavage of ISG15 from interferon responsive factor 3 (IRF3) and attenuates type I interferon responses. Notably, inhibition of SCoV2-PLpro with GRL-0617 impairs the virus-induced cytopathogenic effect, maintains the antiviral interferon pathway and reduces viral replication in infected cells. These results highlight a potential dual therapeutic strategy in which targeting of SCoV2-PLpro can suppress SARS-CoV-2 infection and promote antiviral immunity.

Conflict of interest statement

Competing interests The authors declare no competing interests.

Figures

Extended Data Fig. 1. Biochemical properties of…

Extended Data Fig. 1. Biochemical properties of SCoV2-PLpro.

Extended Data Fig. 2. Complex structure of…

Extended Data Fig. 2. Complex structure of SCoV2-PLpro with mouseISG15.

Extended Data Fig. 3. Sequence alignment of…

Extended Data Fig. 3. Sequence alignment of papain like protease domain from corona viruses.

Extended Data Fig. 4. Structural analysis of…

Extended Data Fig. 4. Structural analysis of GRL-0167, SCoV2-PLpro complex.

Extended Data Fig. 5. Physiological roles of…

Extended Data Fig. 5. Physiological roles of PLpro in cells.

Extended Data Fig. 6. Effect of PLpro…

Extended Data Fig. 6. Effect of PLpro on IFN-β or NF-κB p65 expression level.

Extended Data Fig. 7. Inhibitory effects of…

Extended Data Fig. 7. Inhibitory effects of GRL-0617 on SARS-CoV2 infection.

Fig. 1. DeISGylating and deubiquitylating activities of…

Fig. 1. DeISGylating and deubiquitylating activities of SCoV-PLpro and SCoV2-PLpro.

Fig. 2. Structural analysis of SARS-CoV-2 PLpro…

Fig. 2. Structural analysis of SARS-CoV-2 PLpro in complex with full length ISG15.


The STING ligand 2’3’-cGAMP induces an NF-κB-dependent anti-bacterial innate immune response in the starlet sea anemone Nematostella vectensis

In mammals, the cGAS-cGAMP-STING pathway is crucial for sensing viral infection and initiating an anti-viral type I interferon response. cGAS and STING are highly conserved genes that originated in bacteria and are present in most animals. By contrast, interferons only emerged in vertebrates thus, the function of STING in invertebrates is unclear. Here, we use the STING ligand 2’3’-cGAMP to activate immune responses in a model cnidarian invertebrate, the starlet sea anemone Nematostella vectensis. Using RNA-Seq, we found that 2’3’-cGAMP induces robust transcription of both anti-viral and anti-bacterial genes, including the conserved transcription factor NF-κB. Knockdown experiments identified a role for NF-κB in specifically inducing anti-bacterial genes downstream of 2’3’-cGAMP, and some of these genes were also found to be induced during Pseudomonas aeruginosa infection. Furthermore, we characterized the protein product of one of the putative anti-bacterial genes, the N. vectensis homolog of Dae4, and found that it has conserved anti-bacterial activity. This work describes an unexpected role of a cGAMP sensing pathway in anti-bacterial immunity and suggests that a broad transcriptional response is an evolutionarily ancestral output of 2’3’-cGAMP signaling in animals.

Significance statement Anti-viral immune responses are initiated via signaling pathways such as the STING pathway. In mammals, activation of this pathway results in the production of anti-viral molecules called interferons. Surprisingly, the STING pathway is present in organisms such as sea anemones that lack interferons the function of this pathway in these organisms is thus unclear. Here we report that in the anemone Nematostella vectensis, a small molecule activator of the STING pathway, cGAMP, not only induces an anti-viral response, but also stimulates an anti-bacterial immune response. These results provide insights into the evolutionary origins of innate immunity, and suggest a broader ancestral role for cGAMP-STING signaling that evolved toward more specialized anti-viral functions in mammals.


Characteristics of Populations and Population Change

Population density is the relationship between the number of individuals of a population and the area or volume they occupy. For example, in 2001, the human population density of the United States (according to the World Bank) was 29.71 inhabitants per square kilometer, whereas China had a population density of 135.41 humans per square kilometer.

3. What is the population growth rate?

The population growth rate (PGR) is the percent change between the number of individuals in a population at two different times. Therefore, the population growth rate can be positive or negative.

4. What are the main factors that affect the growth of a population?

The main factors that make populations grow are births and immigration. The main factors that make populations decrease in number are deaths and emigration.

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Migration, Emigration and Immigration

5. How different are the concepts of migration, emigration and immigration?

Migration is the movement of individuals of a species from one place to another. Emigration is migration seen as an the exit of individuals from one region (to another where they will settle permanently or temporarily). Immigration is migration seen as the settling in one region (permanently or temporarily) of individuals coming from another region. Therefore, individuals emigrate "from" and immigrate "to".

6. What are some examples of migratory animals?

Examples of migratory animals are: southern right whales from Antarctica, which reproduce on the Brazilian coast migratory salmon that are born in the river, go to the sea and return to the river to reproduce and die migratory birds from cold regions that spend the winter in tropical regions, etc.

Biotic Potential and Environmental Resistance

7. What is biotic potential?

Biotic potential is the capability for growth of a given population under hypothetical optimum conditions, in an environment without limiting factors for such growth. Under such conditions, the population tends to grow indefinitely. 

8. What is the typical shape of a population growth curve? How can biotic potential be represented in the same way graphically?

A typical population growth curve (number of individuals over time, linear scale) has a sigmoidal shape. There is short and slow initial growth followed by fast and longer period of growth and once again a decrease in growth prior to the stabilization or equilibrium stage.

However, the population growth according to the biotic potential curve  is not sigmoidal it is crescent-shaped and approaches infinity (there is neither a decreasing stage nor an equilibrium).

9. What is environmental resistance?

Environmental resistance is the effect of limiting abiotic and biotic factors that prevent a population from growing as it would normally grow according to its biotic potential. In reality, each ecosystem is able to sustain a limited number of individuals of a given species.

Environmental resistance is an important concept in population ecology.

The Limiting Factors of Population Growth

10. What are the main limiting factors in the growth of a population?

The factors that limit the growth of a population can be divided into biotic factors and abiotic factors. The main abiotic limiting factors are the availability of water and light and the availability of shelter. The main limiting biotic factors are population density and inharmonious (negative) ecological interactions (competition, predatism, parasitism, ammensalism). 

11. How do the availability of water and light and the climate affect the growth of a population?

The availability of water and light along with the climate are abiotic factors that limit the growth of a population. Since producers are responsible for the synthesis of organic material transferred along the food chains of an ecosystem, water and light affect the availability of food and a population cannot grow beyond the number of individuals the environment is able to feed. For example, in the desert, the biomass is relatively small and populations that live in this ecosystem are smaller (compared to the same species in environments with a large available biomass). The climate, including the temperature, affects population growth because excessive change in this factor, such as the occurrence of droughts or floods, may cause a significant decline in a population. Small climatic changes can also alter the photosynthesis rate and reduce the availability of food in the ecosystem.

Predator x Prey Curve

12. How do populations of predators and prey vary in predatism?

Whenever a predator population increases, the prey population tends to decrease at first. Afterwards, the decrease in the prey population and the bigger population density of predators cause the predator population to decrease. The prey population then reverts the decreasing and begins to grow.

If variations in the size of populations occur at an unexpected intensity (different from the usual intensity of the ecological interaction), for example, due to ecological accidents that kill a large amount of prey, the prey-predator equilibrium is disrupted and both species may be harmed. The existence of the predator is sometimes fundamental for the survival of the prey population, since the absence of predatism favors the proliferation of the prey and, in some cases, when excessive proliferation creates a population size beyond the capacity of the ecosystem to sustain them, environmental damage occurs and the entire prey population is destroyed.

Environmental Resistance and Population Growth Curves

13. What is the relationship between environmental resistance and population growth according to the biotic potential curve and the real population growth curve?

The difference between the real population growth curve (number of individuals x time) and population growth according to the biotic potential curve of a given population is a result of environmental resistance.

Bacterial and Viral Population Growth Curves

14. How different is the growth of a viral population according to its biotic potential from the growth of a bacterial population according to its biotic potential?

The growth curves of viruses and bacteria according to their biotic potential both present a positive exponential pattern. The difference between them is that over each time period, bacteria double their population, whereas the viral population multiplies dozens or hundreds of times. Therefore, the viral population growth curve has more intense growth. This happens because bacteria reproduce by binary division, with each cell generating two daughter cells, whereas each virus replicates generating dozens or even hundreds of new viruses.

Age Pyramids

15. What are age pyramids?

Age pyramids are graphical representations in the form of superposed rectangles which each represents the number of individuals included in age ranges into which a population is divided. Generally, the lower age ranges are closer to the bottom of the pyramid, always below the higher ranges, and the variable dimension that represents the number of individuals is the width (however, there are age pyramids in which the variable dimension is the height). 

16. What analysis is provided by the study of human age pyramids?

The study of human age pyramids can provide the following types of analysis: the proportion of individuals at an economically active age the proportion of the elderly (indicating the quality of pension and healthcare systems) the proportion of children and youth (indicating the need for job generation and educational services) the reproductive profile (shows the population growth tendency) the infant mortality rate (indicates the quality of the healthcare system, hygienic conditions, nutrition and poverty) life expectancy etc.

It is possible to predict whether a population belongs to a rich and industrialized society or to a poor country, since the patterns of their age pyramids differ according to these conditions.

17. What are the main characteristics of the age pyramids of developed countries?

In a stabilized human population, the age pyramid has a narrower base, since the birth rate is not so high. The adult age ranges are generally wider than the infantile ranges, showing that, in practice, there is no population growth. There is a proportionally high number of older individuals, meaning that the quality of life is high and that the population has access to healthcare services and good nutrition. These are features of the age pyramids of developed countries.

18. What are the typical features of the age pyramids of underdeveloped countries?

The age pyramids of underdeveloped countries have characteristics related to the poverty of their populations, with a wider base and a narrow tip. The base age range, when much wider than the other levels, indicates a high birth rate. The levels just above the base may present a large reduction in poorer populations due to infant mortality. Ranges that represent youth are also wide, indicating future pressure on job and housing needs. The widths of the rectangles diminish as age increases to the tip, which represents the elderly, demonstrating difficult living conditions, precarious healthcare services and a short life expectancy.

Now that you have finished studying Population Ecology, these are your options:


Persistence of SARS-CoV-2 virus and viral RNA on hydrophobic and hydrophilic surfaces and investigating contamination concentration

The transmission of SARS-CoV-2 is likely to occur through a number of routes, including contact with contaminated surfaces. Many studies have used RT-PCR analysis to detect SARS-CoV-2 RNA on surfaces but seldom has viable virus been detected. This paper investigates the viability over time of SARS-CoV-2 dried onto a range of materials and compares viability of the virus to RNA copies recovered, and whether virus viability is concentration dependant.

Viable virus persisted for the longest time on surgical mask material and stainless steel with a 99.9% reduction in viability by 124 and 113 hours respectively. Viability of SARS-CoV-2 reduced the fastest on a polyester shirt, with a 99.9% reduction within 2.5 hours. Viability on cotton was reduced second fastest, with 99.9% reduction in 72 hours. RNA on all the surfaces exhibited a one log reduction in genome copy recovery over 21 days.

The findings show that SARS-CoV-2 is most stable on non-porous hydrophobic surfaces. RNA is highly stable when dried on surfaces with only one log reduction in recovery over three weeks. In comparison, SARS-CoV-2 viability reduced more rapidly, but this loss in viability was found to be independent of starting concentration. Expected levels of SARS-CoV-2 viable environmental surface contamination would lead to undetectable levels within two days. Therefore, when RNA is detected on surfaces it does not directly indicate presence of viable virus even at high CT values.

Importance This study shows the impact of material type on the viability of SARS-CoV-2 on surfaces. It demonstrates that the decay rate of viable SARS-CoV-2 is independent of starting concentration. However, RNA shows high stability on surfaces over extended periods. This has implications for interpretation of surface sampling results using RT-PCR to determine the possibility of viable virus from a surface. Unless sampled immediately after contamination it is difficult to align RNA copy numbers to quantity of viable virus on a surface.


Author information

Affiliations

CIRAD, UMR PVBMT, St Pierre, La Réunion, France

Computational Biology Division, Department of Integrative Biomedical Sciences, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa

Instituto de Biología Integrativa de Sistemas (I2SysBio), CSIC-UV, Paterna, València, Spain

The Santa Fe Institute, Santa Fe, NM, USA

Research Office, University of Cape Town, Cape Town, South Africa

CIRAD, UMR BGPI, Montpellier, France

BGPI, CIRAD, INRA, Montpellier SupAgro, University of Montpellier, Montpellier, France

The Biodesign Center for Fundamental and Applied Microbiomics, Center for Evolution and Medicine, School of Life Sciences, Arizona State University, Tempe, AZ, USA

Structural Biology Research Unit, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa

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Contributions

P.L., D.P.M., S.F.E., D.N.S., P.R. and A.V. wrote and edited the manuscript. P.L. and A.V. undertook the analyses for the data presented in figures 1–3.

Corresponding author


Jane Flint is Professor Emerita of Molecular Biology at Princeton University. Dr. Flint&rsquos research focused on investigation of the mechanisms by which viral gene products modulate host pathways and antiviral defenses to allow efficient reproduction in normal human cells of adenoviruses, viruses that are used in such therapeutic applications as gene transfer and cancer treatment.

Vincent R. Racaniello is Higgins Professor of Microbiology & Immunology at Columbia University Vagelos College of Physicians & Surgeons. Dr. Racaniello has been studying viruses for over 40 years, including polio- virus, rhinovirus, enteroviruses, hepatitis C virus, and Zika virus. He blogs about virus-es at virology.ws and is host of This Week in Virology.

Glenn F. Rall is a Professor and the Chief Academic Officer at the Fox Chase Cancer Center, and is an Adjunct Professor in the Microbiology and Immunology departments at the University of Pennsylvania, as well as Thomas Jefferson, Drexel, and Temple Universities. Dr. Rall studies viral infections of the brain and the immune responses to those infections, with the goal of defining how viruses contribute to disease.

Theodora Hatziioannou is a Research Associate Professor at Rockefeller University and is actively involved in teaching programs at Albert Einstein College of Medicine. Dr. Hatziioannou has worked on multiple viruses with a focus on retroviruses and the molecular mechanisms that govern virus tropism and on the improvement of animal models for human disease.

Anna Marie Skalka is a Professor Emerita and former Senior Vice President for Basic Research at the Fox Chase Cancer Center. Dr. Skalka is internationally recognized for her contributions to the understanding of the biochemical mechanisms by which retroviruses replicate and insert their genetic material into the host genome, as well as her research into other molecular aspects of retrovirus biology.


Footnotes

↵ 20 Twitter: @SystemsVirology

Conflict of interest: The authors declare that no competing interests exist.

• L452R (in B.1.427/429) and Y453F (in B.1.298) variants in S RBM have emerged

• L452R and Y453F mutants escape from HLA-24-restricted cellular immunity

• L452R increases viral infectivity and potentially promotes viral replication

• Epidemic of L452R-harboring B.1.427/429 variants has been expanding in USA


Viruses: Grade 9 Understanding for IGCSE Biology 1.4

Viruses appear in your syllabus in a section entitled “Variety of Living Organisms”. This is rather unfortunate because of course viruses are not classified as living organisms at all. The reason they are not alive is simple: they are not made of cells and they are incapable of carrying out any metabolic reactions. Viruses are much smaller than any cell, even very small prokaryotic cells such as bacteria.

In the diagram above you can see in the top right of the picture part of a red blood cell. Red blood cells are one of the smaller cells in the human body. The bacterial cell at the bottom of the diagram E.coli is much smaller, and all the blue viruses are much much smaller still. [The units of length on this diagram are nanometers (nm) – a nanometer is 10-9 m]

All viruses are parasitic as they have to infect a living cell in order to reproduce.

What are viruses made of?

Well remember viruses are not made of cells. The individual virus particles are called virions and are simply made up of a protein coat (called a capsid) that encloses some genetic material. The genetic material in a virion can either be DNA or a similar molecule called RNA.

Viruses can infect all different kinds of living organisms. The virus on the left in the diagram above is called a bacteriophage and it infects bacterial cells. You can see the protein coat is arranged into a head, tail and fibres and the genetic material in a bacteriophage is DNA. The virus on the right is the Influenza virus that infects mammals and birds, causing the disease influenza or “flu”. Influenza virus is an RNA virus.

Many human diseases are caused by viral pathogens. Influenza is one (see above) and the other one mentioned in the syllabus is HIV – a virus that causes the diseases AIDS. HIV is also an RNA virus. [HIV stands for Human Immunodeficiency Virus and the disease AIDS is acquired immunodeficiency syndrome.]

Some viruses infect and cause disease in plants. Tobacco Mosaic Virus infects tobacco plants causing yellow leaves as chloroplasts are not formed correctly in the leaves.


Affiliations

State Key Laboratory of Marine Environmental Science, Fujian Key Laboratory of Marine Carbon Sequestration, College of Ocean and Earth Sciences, Xiamen University (Xiang’an), 361102, Xiamen, Fujian, China

Rui Zhang, Yanxia Li, Wei Yan, Yu Wang, Tingwei Luo, Huifang Li & Nianzhi Jiao

Department of Ocean Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China

Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), 519080, Zhuhai, China

Laboratoire d’Océanographie de Villefranche (LOV), UPMC, Université Paris 06, CNRS, Sorbonne Universités, 181 Chemin du Lazaret, 06230, Villefranche-sur-Mer, France


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