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Study of simultaneous virus infection in human respiratory tractLubna Pinky, Hana M. Dobrovolny
Department of Physics and Astronomy, Texas Christian University, Fort Worth, TX
Background• Researchers have found that about 40% of patients hospi-talized with influenza-like illness have more than one viralinfection.
• It is unclear whether simultaneous infections lead to moresevere illness or less severe illness; there is evidence for both.
• Simultaneous RSV and influenza infections are among themost common simultaneous infections.
InfluenzaInfluenza causes thousands of deaths annually and can oc-casionally cause pandemics that can kill millions of people.There are effective vaccines and antivirals for prevention andtreatment of influenza. A typical influenza infection lasts 5to 7 d.
RSVRSV causes severe illness primarily in the elderly and thevery young, but is typically asymptomatic or very mild inhealthy adults. There are currently no vaccines or antiviralsavailable for RSV. A typical RSV infection lasts 7 to 14 d.
Viral replication
Mathematical model
Target cells
Eclipse cells Infectious cells
Infectious cellsEclipse cells
dT
dt= −β1TV1 − β2TV2
dE1
dt= β1TV1 − k1E1
dE2
dt= β2TV2 − k2E2
dI1dt
= k1E1 − δ1I1dI2dt
= k2E2 − δ2I2
dV1dt
= p1I1 − c1V1dV2dt
= p2I2 − c2V2.
• RSV and influenza infect the same cell type.
• We initially neglect cell regeneration — infections are shortcompared to the time it takes for cells to regenerate.
• RSV and influenza cannot both infect the same cell.
• No explicit immune response.
Individual infections
0 2 4 6 8 10Time (dpi)
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Vir
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Influenza
0 2 4 6 8 10Time (dpi)
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Vir
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RSV
• Flu parameters are from Baccam et al. (2008), J. Virol.; RSVparameters are from fits to Bagga et al. (2013), Antivir. Ther.
• Virus is scaled so that both infections reach the same viralpeak.
Combining the infections
0 2 4 6 8 10Time (dpi)
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InfluenzaRSVTotal virus
Dashed line indicates a typical threshold of detection
If started at the same time, with the same initial inoculum,flu is the dominant infection.
Effect of initial inoculum
We varied the initial viral inoculum, either by fixing the fluinoculum and varying RSV inoculum (top row) or vice versa(bottom row).
0 2 4 6 8 10Time (dpi)
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InfluenzaRSVTotal virus
104 times less RSV
0 2 4 6 8 10Time (dpi)
100
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Vir
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iter
InfluenzaRSVTotal virus
102 times less RSV
0 2 4 6 8 10Time (dpi)
100
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102
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105
106
Vir
al t
iter
InfluenzaRSVTotal virus
102 times more RSV
0 2 4 6 8 10Time (dpi)
100
101
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103
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106
Vir
al t
iter
InfluenzaRSVTotal virus
104 times more RSV
0 2 4 6 8 10Time (dpi)
100
101
102
103
104
105
106
Vir
al t
iter
InfluenzaRSVTotal virus
104 times less flu
0 2 4 6 8 10Time (dpi)
100
101
102
103
104
105
106
Vir
al t
iter
InfluenzaRSVTotal virus
102 times less flu
0 2 4 6 8 10Time (dpi)
100
101
102
103
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105
106
Vir
al t
iter
InfluenzaRSVTotal virus
102 times more flu
0 2 4 6 8 10Time (dpi)
100
101
102
103
104
105
106
Vir
al t
iter
InfluenzaRSVTotal virus
104 times more flu
Even if there is a large initial RSV inoculum, RSV cannotprevent flu from taking hold, whereas flu can prevent growthof RSV.
Delayed infection
Simultaneous infections are probably not initiated at thesame time.
0 2 4 6 8 10Time (dpi)
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Vir
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InfluenzaRSVTotal virus
RSV delayed 24 h
0 2 4 6 8 10Time (dpi)
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106
Vir
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iter
InfluenzaRSVTotal virus
RSV delayed 48 h
0 2 4 6 8 10Time (dpi)
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Vir
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iter
InfluenzaRSVTotal virus
RSV delayed 72 h
0 2 4 6 8 10Time (dpi)
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Vir
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iter
InfluenzaRSVTotal virus
RSV delayed 96 h
0 2 4 6 8 10Time (dpi)
100
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Vir
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iter
InfluenzaRSVTotal virus
Flu delayed 24 h
0 2 4 6 8 10Time (dpi)
100
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Vir
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iter
InfluenzaRSVTotal virus
Flu delayed 48 h
0 2 4 6 8 10Time (dpi)
100
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Vir
al t
iter
InfluenzaRSVTotal virus
Flu delayed 72 h
0 2 4 6 8 10 12 14 16 18 20Time (dpi)
100
101
102
103
104
105
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Vir
al t
iter
InfluenzaRSVTotal virus
RSV delayed 96 h
An initial flu infection can block infection RSV. An initialRSV infection does not prevent flu. If the delay is longenough, the flu infection will have a lower viral peak, butwill last longer.
Drug treatment
Effective treatment is currently only available for influenza.If it is used, how does it change the infection? We apply neu-raminidase inhibitor treatment, at an efficacy of 98%, start-ing 1.5 d after the onset of flu and lasting for the remainderof the infection.
0 2 4 6 8 10Time (dpi)
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Vir
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iter
InfluenzaRSVTotal virus
Same amount of flu and RSV
0 2 4 6 8 10Time (dpi)
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Vir
al t
iter
InfluenzaRSVTotal virus
102 times more flu
0 2 4 6 8 10Time (dpi)
100
101
102
103
104
105
106
Vir
al t
iter
InfluenzaRSVTotal virus
102 times more RSV
0 2 4 6 8 10Time (dpi)
100
101
102
103
104
105
106
Vir
al t
iter
InfluenzaRSVTotal virus
Flu delayed 24 h
0 2 4 6 8 10Time (dpi)
100
101
102
103
104
105
106
Vir
al t
iter
InfluenzaRSVTotal virus
RSV delayed 24 h
If flu can grow to high enough viral loads before treatment,it can still block the RSV infection. If it does not quicklyinfect all the available target cells, it can cause a long-lastingRSV infection.
Immunocompromised patients
Since some of our results seem to depend on the fact thatthe viruses are competing for a limited cell population, weexpanded the model to include an unlimited supply of cellsby adding a constant birth rate 1/λ = 30 d to the equationfor target cells. Since we do not have an explicit immuneresponse, this models the infection in immunocompromisedpatients.
0 2 4 6 8 10Time (dpi)
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Vir
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InfluenzaRSVTotal virus
Influenza now becomes a chronic infection (no immune re-sponse), and still beats out RSV when they are started atthe same time with the same initial inoculum.
Effect of initial inoculum
0 2 4 6 8 10Time (dpi)
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Vir
al t
iter
InfluenzaRSVTotal virus
104 times less RSV
0 2 4 6 8 10Time (dpi)
100
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102
103
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105
106
Vir
al t
iter
InfluenzaRSVTotal virus
102 times less RSV
0 2 4 6 8 10Time (dpi)
100
101
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103
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Vir
al t
iter
InfluenzaRSVTotal virus
102 times more RSV
0 2 4 6 8 10Time (dpi)
100
101
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103
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Vir
al t
iter
InfluenzaRSVTotal virus
104 times more RSV
0 2 4 6 8 10Time (dpi)
100
101
102
103
104
105
106
Vir
al t
iter
InfluenzaRSVTotal virus
104 times less flu
0 2 4 6 8 10Time (dpi)
100
101
102
103
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Vir
al t
iter
InfluenzaRSVTotal virus
102 times less flu
0 2 4 6 8 10Time (dpi)
100
101
102
103
104
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Vir
al t
iter
InfluenzaRSVTotal virus
102 times more flu
0 2 4 6 8 10Time (dpi)
100
101
102
103
104
105
106
Vir
al t
iter
InfluenzaRSVTotal virus
104 times more flu
Not even a large inoculum of RSV will overcome the abilityof flu to quickly infect the target cells.
Delayed infection
0 2 4 6 8 10Time (dpi)
100
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Vir
al t
iter
InfluenzaRSVTotal virus
RSV delayed 24 h
0 2 4 6 8 10Time (dpi)
100
101
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103
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106
Vir
al t
iter
InfluenzaRSVTotal virus
RSV delayed 48 h
0 2 4 6 8 10Time (dpi)
100
101
102
103
104
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Vir
al t
iter
InfluenzaRSVTotal virus
RSV delayed 72 h
0 2 4 6 8 10Time (dpi)
100
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103
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105
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Vir
al t
iter
InfluenzaRSVTotal virus
RSV delayed 96 h
0 2 4 6 8 10Time (dpi)
100
101
102
103
104
105
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Vir
al t
iter
InfluenzaRSVTotal virus
Flu delayed 24 h
0 2 4 6 8 10Time (dpi)
100
101
102
103
104
105
106
Vir
al t
iter
InfluenzaRSVTotal virus
Flu delayed 48 h
0 2 4 6 8 10Time (dpi)
100
101
102
103
104
105
106
Vir
al t
iter
InfluenzaRSVTotal virus
Flu delayed 72 h
0 2 4 6 8 10 12 14 16 18 20Time (dpi)
100
101
102
103
104
105
106
Vir
al t
iter
InfluenzaRSVTotal virus
Flu delayed 96 h
A long time delay will allow for an acute RSV infection, buteventually a chronic flu infection will take hold.
Drug treatment
0 2 4 6 8 10 12 14 16 18 20Time (dpi)
100
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Vir
al t
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InfluenzaRSVTotal virus
Same amount of flu and RSV
0 2 4 6 8 10Time (dpi)
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Vir
al t
iter
InfluenzaRSVTotal virus
102 times more flu
0 2 4 6 8 10Time (dpi)
100
101
102
103
104
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106
Vir
al t
iter
InfluenzaRSVTotal virus
102 times more RSV
0 2 4 6 8 10 12 14 16 18 20Time (dpi)
100
101
102
103
104
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106
Vir
al t
iter
InfluenzaRSVTotal virus
Flu delayed 24 h
0 2 4 6 8 10 12 14 16 18 20Time (dpi)
100
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103
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106
Vir
al t
iter
InfluenzaRSVTotal virus
RSV delayed 24 h
If flu can grow to high enough viral loads before treatment,it can still block the RSV infection, leading to no chronicinfection. Otherwise preventing flu leads to a chronic RSVinfection.
Conclusions
• One virus can block another virus through resource com-petition. No viral interactions are necessary.
• Since flu has the higher infection rate, it eats up the avail-able cell population, preventing RSV from taking hold.
• RSV can overcome this handicap to some extent by eitherstarting with a higher inoculum or starting before the flu.
• Even if there is a fresh supply of cells, flu gets to thembefore the RSV leading to chronic flu infections.
• Treating the flu can lead to long-lasting or chronic RSVinfections.
Future Directions
• Investigate the role of cellular coinfection.
• Investigate the role of the immune response.
• Examine other combinations of infectious diseases.
• Compare predictions to experimental data.
• Investigate other forms of regeneration.
